Ocular insert apparatus and methods

ABSTRACT

A comfortable insert comprises a retention structure sized for placement under the eyelids and along at least a portion of conjunctival sac of the upper and lower lids of the eye. The retention structure resists deflection when placed in the conjunctival sac of the eye and to guide the insert along the sac when the eye moves. The retention structure can be configured in many ways to provide the resistance to deflection and may comprise a hoop strength so as to urge the retention structure outward and inhibit movement of the retention structure toward the cornea. The insert may move rotationally with deflection along the conjunctival sac, and may comprise a retention structure having a cross sectional dimension sized to fit within folds of the conjunctiva. The insert may comprise a release mechanism and therapeutic agent to release therapeutic amounts of the therapeutic agent for an extended time.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority of the following U.S. Provisionalpatent applications: (1) U.S. Provisional Application Ser. No.61/534,845, titled “Ocular Insert Apparatus And Methods,” filed on Sep.14, 2011; and (2) U.S. Provisional Application Ser. No. 61/568,624,titled “Ocular Insert Apparatus And Methods,” filed on Dec. 8, 2011. Thedisclosures of the Provisional Patent Applications are herebyincorporated by reference in their entirety.

The subject matter of the present application is related to thefollowing co-assigned patent applications: PCT App. No.PCT/US2010/037268, published as WO2010/141729 on Dec. 9, 2010, entitled“Anterior Segment Drug Delivery”; U.S. patent application Ser. No.13/151,001, filed on Jun. 1, 2010, entitled “Anterior Segment DrugDelivery”; and U.S. Prov. Pat. App. Ser. No. 61/534,845, filed on Sep.14, 2011, entitled “Ocular Insert Apparatus and Methods”, the fulldisclosures of which are incorporated herein by reference.

BACKGROUND

1. Field

Described herein are structures, systems, and methods for placement ofan insert on an eye that may be used to treat the eye. Exemplaryembodiments provide ocular inserts used for drug delivery, along withmethods for using ocular inserts positioned on or near the anteriorsurface of the eye. The exemplary inserts may be worn along an anteriorsurface of the eye outside the optical zone, and can delivertherapeutically efficacious amounts of one or more therapeutic agents.

2. Background

A variety of ophthalmic and non-ophthalmic conditions necessitateadministration of various drugs to the eye. Eye drops and gels can beeffective drug delivery vehicles, but can also have significantdisadvantages. Specifically, eye drops mix with fluid in the tear film,but may have a residence time of only 2-5 minutes in the tear film. Aslittle as 5% of the drug may be absorbed locally; some or all of therest being carried from the lacrimal sac into the lacrimal duct, whichcan have potentially undesirable effects. Consequently, most of the drugmay be wasted with less than ideal amounts delivered to the targetedtissue. Also, the presence of the drug in the bloodstream may havepotentially harmful side effects. Gels may adhere more effectively tothe eye, but can also blur the patient's vision. Both eye drops and gelsmay need to be reapplied frequently for some therapies, and patients maynot administer the eye drops or gels as frequently as directed in atleast some instances, such that the amount of drug delivered can be lessthan ideal. For example, in at least some instances a substantial numberof patients may not refill their prescription after one year, and thesubstantial number of patients can be up to fifty percent in someinstances. Thus, a need remains for improved drug delivery to the eyehaving less frequent user application and providing improved regularityof the amount of drug delivered to the eye. Another potentialdisadvantage of topically applied drops and gels can be that such bolusdosing may result in hyperemia and irritation of ocular tissue in atleast some instances.

In light of the disadvantages of eye drops, it is understandable that avariety of alternatives have been proposed. Among the known prioralternatives to drops include treatments in which insert structurescontaining or impregnated with drugs have been placed under an eyelid,in a punctum, or on the cornea with drug-impregnated contact lenses, andthe like.

Although such prior insert structures appear to present significantpotential advantages over drop-administered drug treatment of the eye,the prior approaches with insert structures can provide less than idealresults in at least some instances. Although intravitreal andintraocular implants have been proposed, such implants can be moreinvasive that would be ideal in at least some instances. While punctualplugs can be less invasive, the amount of therapeutic agent availablefor sustained release can be less than ideal in at least some instances.The clinical acceptance of the prior insert structures has been lessthan ideal, and many drugs continue to be delivered to the front of theeye with drops. Clinical studies with prior insert structures appear tohave shown that in at least some instances the prior insert structuresmay not work as well as would be ideal for at least some patients of apatient population. Factors that may have contributed to the limitedacceptance of prior ocular inserts include: a lack of efficacy, a lackof comfort, propensity for displacement or movement from a desiredposition on the eye, incidents of inadvertent expulsion during sleep orrubbing of the eye, interference with vision, and difficulty withplacement and removal. For example, in at least some instances the priorinsert structures may not be retained in the eye as long as would beideal, resulting in less than ideal amounts of the drug delivered to theeye. In at least some instances, the force of the eyelids, eye movement,change in insert position, or eye rubbing may not keep the prior insertsin the eye and the force of the eyelid may expel the insert from theeye. The prior insert devices can be less comfortable than would beideal, and in at least some instances blinking of the eye may cause theinsert to touch the cornea, or rub against the palpebral or bulbarconjunctiva, resulting in discomfort for the patient in at least someinstances. Further, assuming the prior insert structure can be retainedin the eye for the extended time, the amount of drug released and therelease rate profile of the amount released for the extended time can beless than ideal for at least some of the prior insert structures in atleast some instances.

In light of the above, new drug delivery devices, systems, and methodswould be beneficial, particularly for delivering therapeutic agents tothe anterior segment of the eye. It would be particularly advantageousto provide improved ocular inserts which are configured as to gaingreater acceptance from both physicians and users, with such insertsideally being easier to insert and remove, providing greater retentionand compliance with a population of patients, providing greater patientcomfort while remaining on the eye for an extended time, being non-toxicand not interfering with vision, and the like. It would also bedesirable to provide improved ocular inserts which would provideimproved amounts of release, release profiles and pharmacokineticsthroughout long term use, including providing safe, efficient andreproducible local therapeutic agent release from the device withlimited systemic or localized side effects and effective transportationto and absorption by tissues that provide therapeutic benefits, ideallywhile being relatively easy to manufacture at a reasonable price.

SUMMARY

Embodiments are generally provided for improved inserts and methods forplacement on the conjunctiva of the eye, such that the inserts can beretained on the eyes of many patients for an extended time. Although,specific reference is made to drug-delivery devices and associatedmethods, embodiments can be used with many applications where it wouldbe helpful to retain a structure on the eye. Many embodiments provide anocular insert to deliver a therapeutic agent that can be comfortablyplaced at many locations of the conjunctiva, including along at least aportion of the conjunctival sac. The insert can move when placed on theconjunctiva and can be retained with the eye so as to provide improvedcomfort for the patient. The insert may comprise a resistance todeflection to retain the insert comfortably within the eye. The insertcan be configured in many ways to provide the resistance to deflection.The insert may comprise a matrix comprising a therapeutic agent and theresistance to deflection, and the matrix may comprise a materialproviding the resistance to deflection. Alternatively or in combination,the insert may comprise a retention structure and a support structurecoupled to the retention structure, in which the support structure maycontain the therapeutic agent. The retention structure may comprise aninner structure with the support structure comprising the therapeuticagent covering at least a portion of the retention structure, or theretention structure may comprise an outer structure covering at least aportion of the support structure comprising the therapeutic agent.

The insert may be configured such that the insert can be deflectedduring insertion and removal and may comprise the resistance todeflection for comfort and retention. The insert comprising theresistance to deflection can be comfortably placed at one or more ofmany locations of the conjunctiva, such that many patients can betreated comfortably and the placement can be adjusted based on theanatomy of the patient and physician preference. The insert may comprisethe resistance to deflection such that the conjunctiva can be shapedwith the insert so as to receive the insert, and in many embodiments theinsert may comprise an amount of resistance to form one or more of afold, a pocket, or deformation of the conjunctiva so as to receive andretain the insert. The one or more locations where the insert can beplaced include the inferior conjunctival sac, an inferior temporallocation of the conjunctival sac, an inferior nasal location of theconjunctival sac, the superior conjunctival sac, portions of the upperand lower conjunctival sacs near lateral canthus of the palpebralfissure, portions of the upper and lower conjunctival sacs near themedial canthus and caruncle. These areas are well suited to receivestructures having relatively large volumes for extended release of oneor more therapeutic agents.

The insert can be configured in many ways to treat a patient with atherapeutic agent for an extended time, and may comprise one or more ofa high dose of therapeutic agent, a substantial surface area to releasethe therapeutic agent, a hoop strength to resist deflection, a bendingstrength to resist deflection, a shape profile to fit the eye, or abiasing curve to retain the insert, and combinations thereof. The insertmay comprise biasing shape so as to retain the insert, for example witha curve, bend, or other deflected shape to retain the insert. Thebiasing shape may comprise a resiliently curved biasing spring structureshaped to provide force in response to deflection so as to urge one ormore of the first portion or the second portion toward the eye to retainthe insert.

The insert can be sized and shaped for placement under the eyelids andalong at least a portion of a conjunctival sac of the upper and lowerlids of the eye, or combinations thereof. The insert can be sized andshaped so as to move within the conjunctival sac of the eye and be heldon the eye without attachment to the eye so as to provide improvedcomfort. The insert may comprise a preformed shape profile correspondingto a curved shape profile of the eye extending away from a plane, suchthat the insert can resist deflection away from bulbar conjunctivatoward the plane when placed. The insert can be configured to deflectwhen placed in the conjunctival sac of the eye and guide the insertalong the sac when the eye moves with one or more of rotation orcyclotorsion. The insert may also comprise resistance to deflection soas to urge the insert outward and inhibit movement of the retentionstructure toward the cornea. The insert may comprise a first portionhaving a first resistance to deflection and a second portion having asecond resistance to deflection less than the first portion, such thatfirst portion can resist deflection of the upper lid and the secondportion can fit within the one or more folds of the lower lid. The firstportion and the second portion may comprise a similar material, and thefirst portion may have a cross sectional size greater than the secondportion to provide the increased resistance to deflection, and theincreased cross sectional size of the first portion may help to retainthe first portion with the upper lid. Alternatively or in combination,the increased cross-sectional size of the first portion may provideanchoring under the upper lid. The insert may move rotationally withdeflection along the conjunctival sac such that the retention structurecan slide along the conjunctival sac about an axis of rotation passingthrough the iris and the pupil of the eye. In many embodiments theinsert can allow sliding movement along the conjunctiva in response totorsional or other movement of the eye so as to improve comfort for thepatient.

The insert can be configured in many ways to provide the resistance todeflection. The insert may comprise a retention structure providing amajority of the resistance to deflection. Alternatively, the insert canbe configured to provide the resistance to deflection without aretention structure, and in many embodiments may comprise with a drugdelivery matrix configured to provide the resistance to deflection suchthat the insert can be provided without the retention structure.

The eye comprises upper and lower conjunctival sacs corresponding to theupper eyelid and the lower eyelid, and each of the upper and lowerconjunctival sacs comprises a bulbar portion of conjunctiva and apalpebral portion of conjunctiva. The bulbar portion and the palpebralportion of each sac may comprise a plurality of folds, and the insertmay comprise a resistance to deflection so as to shape the conjunctivaand form one or more of an indentation, a deformation, a fold or apocket of the conjunctiva. The insert can be elongate and sized toextend a substantial distance along the shaped conjunctiva, such thatthe retention structure can be held with the one or more of theindentation, the deformation, the fold or the pocket of the conjunctiva.The palpebral and bulbar conjunctiva may each be shaped with theretention structure so as to comprise one or more folds or pockets, andthe insert can extend substantially along the one or more folds orpockets such that the retention structure can move with the eye. Theshaped conjunctival tissue may comprise tissue of the formix, orconjunctival tissue located away from the formix, or combinationsthereof. The movement of the insert along the conjunctival sac,resistance to inward deflection, resistance to deflection to shape theconjunctiva can provide improved comfort for the patient.

The insert may comprise an amount of therapeutic agent sufficient torelease therapeutic amounts of the therapeutic agent for an extendedtime, and the insert can be configured in many ways so as to release thetherapeutic amounts for the extended time. The therapeutic agent may becontained in a matrix having inclusions of the therapeutic agent, and asurface area of the matrix can be sized to release the therapeuticamounts for the extended time. The insert may comprise a lubricouscoating on one or more of the retention structure or the supportstructure, and the therapeutic agent may be released from the surfacethrough the lubricous coating. The therapeutic amounts of thetherapeutic agent may be substantially released at intervals with one ormore of an erodible material or a pump, which may provide increasedefficacy of at least some therapeutic agents such as prostaglandins. Thetherapeutic agent can be released at intervals with pulsatile flow froma pump such as an osmotic pump, and the pump may be coupled to acontainer comprising inclusions of the therapeutic agent so as torelease solubilized therapeutic agent with pulsatile flow and inhibitrelease of the inclusions. Alternatively, an inner drug delivery matrixhaving a therapeutic agent loaded thereon may comprise the retentionstructure, and an outer structure provided over the inner drug deliverymatrix, in which the outer structure comprises a rate limitingstructure, a structure to provide comfort, or combinations thereof.

The retention structure can be configured in many ways to provideincreased comfort for the patient, and can be placed in many ways. Theretention structure may comprise soft material at locationscorresponding to one or more of the lacrimal gland or the caruncle, andcan be shaped to inhibit contact with tissue near one or more of thelacrimal gland or the caruncle. Although the retention structure maycomprise one or more of many shapes such as circular, oval, serpentine,saddle shaped, cylindrical or toric, the retention structure maycomprise one or more portions shaped to inhibit irritation to thelacrimal gland and the caruncle. The retention structure can be shapedto inhibit contact with the conjunctiva covering the lacrimal gland, andthe retention structure may comprise an extension shaped to extendaround the lacrimal gland. The extension can extend inward toward thepupil around the lacrimal gland, or outward away from the pupil aroundthe lacrimal gland. The retention structure may comprise a portionshaped to extend away from the caruncle when placed, such as an inwardextension.

Additional aspects are recited in the claims below, and can provideadditional summary in accordance with embodiments described herein. Itis contemplated that the embodiments as described herein and recited inthe claims may be combined in many ways, and any one or more of theelements recited in the claims can be combined together in accordancewith embodiments and teachings as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows a side sectional view of an eye suitable for combinationwith an insert, in accordance with an embodiment;

FIG. 1B shows front view of the eye as in FIG. 1A, in accordance with anembodiment;

FIG. 1C side sectional view of the conjunctiva of the upper and lowerlids of the eye as in FIGS. 1A and 1B, in accordance with an embodiment;

FIG. 1D shows a side sectional view of the upper lid of the eye as inFIGS. 1A to 1C and the folds of the conjunctiva, in accordance with anembodiment;

FIG. 1E shows muscles of a pair of eyes that provide cyclotorsion of theeye suitable for combination with an ocular insert, in accordance withan embodiment;

FIG. 1-1-2 shows an anatomical tissue structure of an eye suitable fortreatment with ocular inserts;

FIG. 1-2-1 shows an embodiment of a therapeutic system comprising anocular insert, that may also include an insertion device, aconfiguration altering material that dissolves (or swells, weakens,tightens, or effects some other activation mechanism) to reconfigure theimplant from an insertion configuration to a deployed configuration, orthe like;

FIGS. 1-2-2 and 1-2-3 show a top view and cross-sectional view of thetherapeutic system shown in FIG. 1-2-1;

FIG. 1-2-4 shows an embodiment of the therapeutic system where the ringcomprises two radially outwardly and/or anteriorly extending protrusionsor bumps on opposed portions of its surface;

FIG. 1-2-5 shows an alternative embodiment of the ring-shapedtherapeutic device system. In this embodiment, a crescent orbanana-shaped reservoir is attached to the inferior portion of theocular insert;

FIGS. 1-3-1 to 1-3-3 show another embodiment of the therapeutic systemincluding a ring-shaped structure with a diameter of at least 8 mm,sized to fit outside the optical zone of the cornea, and also having twoor more haptics;

FIGS. 1-4-1 to 1-4-2 show an alternate embodiment of the therapeuticsystem in which two or more concentric ring-shaped structures are heldtogether by four or more haptics;

FIG. 1-4-3 shows an embodiment that employs an eccentric design suchthat the one or more ring portions or arc segments are present in theinferior area of the ring to target delivery to the area of the eyewhere tears may more readily pool, as in the cul-de-sac;

FIGS. 1-5-1 through 1-5-3 show a serpentine embodiment of therapeuticsystem which shows an expandable ocular insert;

FIGS. 1-6-1 and 1-6-2 show another embodiment where the secondcushioning structure comprises two hydrogel scleral contact lensesattached to each other, so as to sandwich the first rigid structurebetween them;

FIG. 1-7-1 shows a close-up of an exemplary ocular insert of thetherapeutic device system in which the second structure is disposedthroughout the circumferential length of the first structure;

FIG. 1-7-2 shows a cross-section of a therapeutic device systemcomprising a second structure with a tapered outer and/or inner edge;

FIG. 1-7-3 shows a cross-section of a therapeutic device systemcomprising a second structure with a beveled edge;

FIG. 1-7-4 shows a cross-section of a therapeutic device systemcomprising a second structure with a rounded edge;

FIG. 1-8-1 shows a therapeutic device system with a second structurethat may have an anterior and/or posterior surface that can be shaped aswell to the radius of curvature of the eye;

FIG. 1-9-1 shows the second, cushioning structure disposed over discreteportions of the length of the first supporting structure;

FIG. 2A shows an insert for insertion into an eye, in accordance with anembodiment;

FIG. 2B shows a cross sectional view of a retention structure, inaccordance with an embodiment;

FIG. 2C shows an insert as in FIGS. 2A and 2B deflected in response toplacement in an eye and corresponding force to urge the retentionstructure outward, in accordance with an embodiment;

FIG. 2C1 shows a retention structure self-loaded and deflected at anangle, in accordance with an embodiment;

FIG. 2C2 shows torsion of a retention structure at a first location atresistance to twisting, in accordance with an embodiment;

FIG. 2D shows an insert having a preformed oval shape extending along aconvex spherical surface, such that the insert extends away from a planeand resists deflection toward the plane, in accordance with anembodiment;

FIG. 2E shows a view of an insert as in FIG. 2D extending alongnasal-temporal and anterior posterior directions, in accordance with anembodiment;

FIG. 2F shows a side view of an insert as in FIG. 2D extending alongsuperior-inferior and anterior posterior directions, in accordance withan embodiment;

FIG. 2G shows an insert having a preformed oval shape extending along aconvex spherical surface and in which the oval ring has a first portioncorresponding to the upper conjunctival sac and a second portioncorresponding to the lower conjunctival sac, in which the second portioncorresponding to the lower conjunctival sac has a thinner cross sectionthan the first portion corresponding to the upper conjunctival sac, suchthat the ring extends away from a plane and resists deflection towardthe plane and places the second portion on the bulbar conjunctiva whenthe first portion is retained with the upper lid, in accordance with anembodiment;

FIG. 2H shows an insert comprising a support structure and a retentionstructure having a preformed oval shape extending along a convexspherical surface, such that the insert extends away from a plane andresists deflection toward the plane, in accordance with an embodiment;

FIG. 2I shows a top view of an insert as in FIG. 214 extending alongnasal-temporal and anterior posterior directions, in accordance with anembodiment;

FIG. 2J shows an insert comprising a support structure and a retentionstructure having a preformed curved annular shape corresponding to theeyelid, such that the insert extends away from a plane and resistsdeflection toward the plane, in accordance with an embodiment;

FIG. 2K shows a top view of an insert as in FIG. 2J extending alongnasal-temporal and anterior posterior directions and having thepreformed curved surface corresponding to the eyelid along the nasaltemporal direction to fit the eye, in accordance with an embodiment;

FIG. 2L shows an insert comprising a retention structure comprisinghinge portion and a stiff portion having a preformed curved annularshape corresponding to the eyelid, such that the insert extends awayfrom a plane and resists deflection toward the plane, in accordance withan embodiment;

FIG. 2M shows a top view of an insert as in FIG. 2L extending alongnasal-temporal and anterior posterior directions and having the stiffpreformed curved surface corresponding to the eyelid along the nasaltemporal direction to fit the eye, in accordance with an embodiment;

FIG. 2N shows an isometric view of an insert having a 3-D shape profilecorresponding to a saddle having positive curvature along the nasal andtemporal portions and opposing negative curvature along the inferior andsuperior portions, such that the nasal and temporal portions areposterior to the inferior and superior portions when placed, inaccordance with an embodiment;

FIG. 2O shows an isometric view of an insert having a 3-D shape profilecorresponding to a saddle having negative curvature along the nasal andtemporal portions and opposing positive curvature along the inferior andsuperior portions, such that the nasal and temporal portions areanterior to the inferior and superior portions when placed, inaccordance with an embodiment;

FIG. 2P1 shows an insert comprising a retention structure having anupper portion comprising a first durometer and a lower portioncomprising a second durometer, in accordance with an embodiment;

FIG. 2P2 shows an insert comprising a retention structure having anupper portion and a lower portion in which the lower portion is curvedinward toward the eye, for example with a lower bend, in accordance withan embodiment;

FIG. 2P3 shows an insert comprising a retention structure having ahinges to couple an upper portion to a lower portion and allow the upperportion to swing toward the lower portion, in accordance with anembodiment;

FIG. 2P4 shows an insert comprising a retention structure having a firstupper portion and a second lower portion with bias curve such that theupper and lower portions extend posteriorly to the nasal and temporalportions prior to placement, in accordance with an embodiment;

FIG. 2P5 shows an insert comprising a retention structure having a firstupper portion and a second lower portion with bias curve such that theupper and lower portions extend anteriorly to the nasal and temporalportions prior to placement, in accordance with an embodiment;

FIG. 2P6 shows an insert comprising a retention structure having anoblong shape and having first upper portion and a second lower portionin which the upper portion comprises an elongate oval shape portion toextend into the upper formix and the lower portion comprises a shorterwider oval shape to extend into the lower formix, in accordance with anembodiment;

FIG. 2P7 shows an insert comprising a retention structure comprising anupper portion and a lower portion coupled with hinges so as to define anelliptical shape, in accordance with an embodiment;

FIG. 2P8 shows an insert comprising a flexible redundant retentionstructure to seat the retention structure in the eye, in accordance withan embodiment;

FIG. 2P9 shows an insert comprising an upper anchor, in accordance withan embodiment;

FIG. 2P10 shows an insert comprising a lower anchor to resist pull ofthe round structure, in accordance with an embodiment;

FIG. 2Q shows an insert comprising a retention structure configured toexert at least some pressure on the conjunctiva to retain the insert, inaccordance with an embodiment;

FIG. 2R shows an insert comprising a retention structure having a curvedportion to extend laterally to the temporal formix of the eye, inaccordance with an embodiment;

FIG. 2S shows an insert comprising a retention structure having an outercurved portion to extend laterally to the temporal formix of the eye, inaccordance with an embodiment;

FIG. 2T shows an insert comprising a retention structure having an outeranchor portion to extend laterally to the temporal formix of the eye, inaccordance with an embodiment;

FIGS. 2U and 2V show an insert comprising a retention structure havingan upper portion sized to extend into the upper formix and a lowerportion sized to extend into a lower formix with an intermediate portionbetween the upper and lower portions and wherein the upper and lowerportions curve posteriorly from the intermediate portion to fit theupper and lower formices, respectively, in accordance with anembodiment;

FIG. 2W shows an insert comprising an upper portion comprising ahydrophilic surface and a lower portion comprising a hydrophobicsurface, in accordance with an embodiment;

FIGS. 2X1 and 2X2 show front and side views, respectively, of an insertcomprising an upper portion and a lower portion and a stiff portions toangularly bias the upper portion and the lower portion toward eachother, in accordance with an embodiment;

FIG. 2Y shows an insert comprising an expandable retention structure toallow the insert to be stretched to fit the eye, in accordance with anembodiment;

FIG. 2Z1 shows an insert comprising a retention structure having anupper portion and a lower portion coupled with a variable joint to as tovary a size of the retention structure and insert, in accordance with anembodiment;

FIG. 2Z2 shows a telescopic joint of an insert as in FIG. 2Z1, inaccordance with an embodiment;

FIG. 2Z3 shows a shock absorbing spring joint of an insert as in FIG.2Z1, in accordance with an embodiment;

FIG. 2Z4 shows a ratcheting joint of an insert as in FIG. 2Z1, inaccordance with an embodiment;

FIGS. 2Z5 and 2Z6 show front and side views, respectively, of an insertcomprising an elongate shape having upper and lower portions sized toextend into upper and lower formices, respectively, so as to providesubstantially greater amounts of therapeutic agent than the intermediateportions locatable near the lateral and medial canthus, in accordancewith an embodiment;

FIGS. 2Z7 and 2Z8 show front and side views, respectively, of a rigidinsert having a curved shape sized to fit the eye of the patient suchthat the insert can be worn comfortably for an extended time, inaccordance with an embodiment;

FIG. 3A1 shows an insert placed between folds of conjunctiva, inaccordance with an embodiment;

FIG. 3A2 shows a fold of conjunctiva receiving an insert, in accordancewith an embodiment;

FIG. 3A3 shows an insert sized to fit between folds of conjunctiva, inaccordance with an embodiment;

FIG. 3A4 shows a retention structure of an insert as in FIGS. 2A to 2Gplaced on an eye such that the retention structure has fit into one ormore of a plurality of folds of the bulbar conjunctiva, in accordancewith an embodiment;

FIG. 3B shows a retention structure under a fold of bulbar conjunctiva,in accordance with an embodiment;

FIGS. 3C1 to 3C3 show a retention structure under a fold of bulbarconjunctiva moving with rotation of the eye, in accordance with anembodiment;

FIG. 3D shows an initial inferior placement of an insert comprising aretention structure, in accordance with an embodiment;

FIG. 3E show an insert initially placed as in FIG. 3D which has movedrotationally along the conjunctiva about an axis of rotation extendingthrough a pupil of the eye, in accordance with an embodiment;

FIG. 3F shows the an insert located at an inferior temporal location ofthe conjunctiva of the eye and the orbit, in accordance with anembodiment;

FIG. 3G shows the support structure placed superiorly, in accordancewith an embodiment;

FIG. 3G-1 shows the support structure placed superiorly at an initiallocation of the superior conjunctival sac, in accordance with anembodiment;

FIG. 3G-2 shows the support structure seated in the cul-de-sac of thesuperior conjunctival sac following placement as in FIG. 3G-1, inaccordance with an embodiment;

FIG. 3H shows the support structure located at an inferior nasallocation of the eye so as to extend near the caruncle, in accordancewith an embodiment;

FIG. 3I shows the support structure placed at a temporal location of theeye, in accordance with an embodiment;

FIG. 3J shows retention structure comprising a first portion having afirst resistance to deflection and a second portion having a secondresistance to deflection less than the first portion, in accordance withan embodiment;

FIG. 3J-1 shows a side cross sectional view of the retention structureas in FIG. 3J, in accordance with an embodiment;

FIG. 3K shows an insert comprising a support structure comprising amatrix of therapeutic agent on the retention structure as in FIG. 3J, inaccordance with an embodiment;

FIG. 3L shows an insert comprising a lubricous coating, in accordancewith an embodiment;

FIG. 3L-1 shows a layer of the lubricous coating on the surface of thematrix containing the therapeutic agent as in FIG. 3L, in accordancewith an embodiment;

FIG. 4A shows an insert comprising a plurality of therapeutic agentsloaded on a first portion of the support structure and a second portionof the support structure, in accordance with an embodiment;

FIG. 4B shows a matrix comprising inclusions of a therapeutic agent, inaccordance with an embodiment;

FIG. 4C shows a plurality of support structures comprising a pluralityof therapeutic agents placed together on a retention structure at alocation corresponding to placement along an inferior temporal portionof the conjunctiva of the eye, in accordance with an embodiment;

FIG. 4D shows a plurality of support structures along a retentionstructure, in accordance with an embodiment;

FIG. 4E shows release of a therapeutic agent from a matrix having asurface area sized to treat the patient for an extended time, inaccordance with an embodiment;

FIG. 4F shows release of a therapeutic agent from a spherical surface ofa spherical matrix structure located on a retention structure, in whichthe spherical surface has an area to release therapeutic amounts of thetherapeutic agent for the extended time, in accordance with anembodiment;

FIG. 4G shows a plurality of at least three support structures along aretention structure comprising a plurality of at least three therapeuticagents, in accordance with an embodiment;

FIG. 4G-1 shows a plurality of support structures comprising a firsttherapeutic agent contained within a first matrix and a secondtherapeutic agent contained within a second matrix, in accordance withan embodiment;

FIG. 4G-2 shows a retention structure comprising a ring, the ringcomprising a plurality of ring segments, in accordance with anembodiment;

FIG. 4G-3 shows an annular insert comprising a retention structurecomprising an annular ring and an annular support comprising a matrix oftherapeutic agent covering the retention structure, in accordance withan embodiment;

FIG. 4G-4 shows a cross-sectional view of the retention structure andsupport structure of FIG. 4G-3, in accordance with an embodiment;

FIG. 4H shows an insert comprising a structure having an erodiblematerial to release a therapeutic agent for an extended time, inaccordance with an embodiment;

FIG. 4I shows a transverse cross sectional view of the structurecomprising the erodible material as in FIG. 4H, in accordance with anembodiment;

FIG. 4J shows a side cross sectional view of the structure comprisingthe erodible material as in FIGS. 4H and 4I, in accordance with anembodiment;

FIG. 4K shows a container having a channel occluded with an erodiblematerial as in FIGS. 4H to 4J, in accordance with an embodiment;

FIG. 4L shows the container as in FIG. 4K having the material erodedaway from the channel to release the therapeutic agent, in accordancewith an embodiment;

FIG. 4M shows a pump to release a therapeutic agent with pulsatile flow,in accordance with an embodiment;

FIG. 4N shows a release profile of therapeutic agent of the pump as inFIG. 4M, in accordance with an embodiment;

FIG. 4O shows a pressure profile of a chamber of the pump as in FIGS. 4Mand 4N, in accordance with an embodiment;

FIG. 4P shows reservoir chamber comprising inclusions of a therapeuticagent coupled to an osmotic pump with a piston so as to releasetherapeutic agent with pulsatile flow, in accordance with an embodiment;

FIG. 4Q shows reservoir chamber comprising inclusions of a therapeuticagent coupled to valve of an osmotic pump so as to release therapeuticagent with pulsatile flow, in accordance with an embodiment;

FIG. 5A shows an insert comprising a lentoid retention structure havingan end portion shaped to inhibit contact with the caruncle of the eyewhen the support structure comprising the therapeutic agent is placed onthe inferior temporal location of the eye, in accordance with anembodiment;

FIG. 5B shows an insert comprising a lentoid retention structure havingdecreased width to inhibit contact with the caruncle of the eye when thesupport structure comprising the therapeutic agent is placed on theinferior temporal location of the eye, in accordance with an embodiment;

FIG. 5C shows an insert comprising a retention structure shaped with aninward extension to inhibit irritation of the lacrimal gland and aninward extension to inhibit contact with the caruncle of the eye, inaccordance with an embodiment;

FIG. 5D shows an insert comprising a retention structure shaped with anoutward extension to inhibit irritation of the lacrimal gland of theeye, in accordance with an embodiment;

FIG. 5E shows an insert comprising a retention structure shaped with aninward extension to inhibit irritation of the lacrimal gland of the eye,in accordance with an embodiment;

FIG. 5F shows an insert comprising a retention structure having an openend portion to inhibit irritation of the lacrimal gland of the eye, inaccordance with an embodiment;

FIG. 5G shows an insert comprising a retention structure having a softmaterial to inhibit irritation of the lacrimal gland and the caruncle ofthe eye, in accordance with an embodiment;

FIG. 5H shows a retention structure comprising an open end portion toinhibit irritation of the lacrimal gland and an inward extension portionto inhibit contact with the caruncle of the eye, in accordance with anembodiment;

FIG. 5I shows a retention structure comprising an inward extensionportion to inhibit contact irritation of lacrimal gland and an open endportion to inhibit contact with the caruncle of the eye, in accordancewith an embodiment;

FIG. 5J shows an insert comprising a retention structure shaped with aninward extension to inhibit irritation of the lacrimal gland and aninward extension to inhibit contact with the caruncle of the eye, inwhich the support structure is located on the retention structure so asto correspond with a superior placement under the superior eyelid, inaccordance with an embodiment;

FIG. 6A shows an insert comprising a lentoid retention structure havingan open end portion to inhibit contact with the caruncle of the eye whenplaced on the eye with the support structure comprising the therapeuticagent placed on the inferior temporal location, in accordance with anembodiment;

FIG. 6B shows an insert comprising a circular retention structure havingan open portion to inhibit contact with the caruncle of the eye whenplaced on the eye with the support structure comprising the therapeuticagent placed on the inferior temporal location of the eye, in accordancewith an embodiment;

FIG. 6C shows an insert comprising a round retention structure havingfirst support structure comprising a first therapeutic agent at a firstlocation corresponding to an inferior temporal location of the eye and asecond support structure comprising a second therapeutic agent at asecond location corresponding to a superior location of the eye, inaccordance with an embodiment;

FIG. 6D shows an insert comprising a round retention structure having anopen end and a first support structure comprising a first therapeuticagent at a first location corresponding to an inferior temporal locationof the eye and a second support structure comprising a secondtherapeutic agent at a second location corresponding to a superiorlocation of the eye, in accordance with an embodiment;

FIGS. 7A and 7B show plan and side cross-sectional views, respectively,of an insert comprising an outer retention structure having a resistanceto deflection to remain within the eye for an extended time, inaccordance with an embodiment;

FIGS. 7C and 7D show plan and side cross-sectional views, respectively,of an arcuate C-shaped insert comprising an outer retention structurehaving a resistance to deflection to remain within the eye for anextended time, in accordance with an embodiment;

FIG. 8A shows treatment of a retention structure of an insert toincrease a resistance to deflection of the retention structure, inaccordance with an embodiment;

FIG. 8B shows in situ forming of a retention structure of an insert, inaccordance with an embodiment;

FIG. 8C shows a flowable material placed on the eye to form at least aportion of the insert, in accordance with an embodiment;

FIG. 8D depicts syringe system 300 with barrel 302, needle hilt 303,needle 304 with rounded tip 306 having outlet 308 and plunger 310 withpusher 312, in accordance with an embodiment;

FIG. 8E shows a syringe system being used to introduce hydrogelprecursors into the cul-de-sac, for example into the formix, with theprecursors left in on or more of the cul-de-sac or the formix, inaccordance with an embodiment;

FIG. 9 shows a kit comprising a plurality of retention structures havingincrementally increasing sizes to determine a size of the retentionstructure to fit the patient, in accordance with an embodiment;

FIG. 10 shows a measurement apparatus to measure a dimension ofstructure of the patient to determine a corresponding size of theretention structure to fit the patient, in accordance with anembodiment;

FIG. 10A shows a measurement apparatus to measure a depth of theconjunctival sac of the patient to determine a corresponding size of theretention structure to fit the patient, in accordance with anembodiment;

FIGS. 11A and 11B show a patient looking to a first side and a secondside, respectively, to determine a dimension of the eye, in accordancewith an embodiment;

FIGS. 12A1 and 12A2 show plan and side views, respectively, of theinsert having a therapeutic agent and at least one opticallytransmissive portion and at least one visible portion, in accordancewith an embodiment;

FIGS. 12B1 and 12B2 show insert 100 comprising second configuration100C2, in accordance with an embodiment;

FIGS. 13A1 and 13A2 show a support structure configured to resistmovement away from the inferior temporal portion of the conjunctivalsac, in accordance with an embodiment;

FIGS. 13B1 and 13B2 show insert 100 comprising second configuration100C2, in accordance with an embodiment;

FIGS. 14A1 and 14A2 show plane and side views, respectively, ofstructure comprising a first structure and a second structure spacedapart with distance to maintain the first structure and the secondstructure in the inferior temporal location of the conjunctival sac, inaccordance with an embodiment;

FIGS. 14B1 and 14B2 show the insert 100 placed along at least a portionof the conjunctival sac of an eye, in accordance with an embodiment;

FIG. 15 shows insert comprising a C-shaped configuration with retentionstructure comprising a first end and a second end, in accordance with anembodiment;

FIG. 16A shows an insert comprising a therapeutic agent of matrix and asecond therapeutic agent of a second matrix, in accordance with anembodiment;

FIG. 16B shows a cross sectional view of an insert as in FIG. 16A, inaccordance with an embodiment;

FIG. 16C shows an insert comprising extensions to release a therapeuticagent, in accordance with an embodiment;

FIG. 16D shows a retention structure comprising a matrix containing atherapeutic agent, in accordance with an embodiment;

FIG. 16E shows an insert comprising a support structure havingextensions to release therapeutic agent away from the retentionstructure, in accordance with an embodiment;

FIG. 16F shows a side cross sectional view of an insert comprising asupport structure having extensions to release therapeutic agent awayfrom the retention structure as in FIG. 16E, in accordance with anembodiment;

FIG. 16G shows a support structure comprising a plurality of outwardextensions to increase a surface area of the matrix to release thetherapeutic agent, in accordance with embodiments;

FIG. 17A shows a mold to make the insert comprising a first componentand a second component, in accordance with an embodiment;

FIG. 17B shows the mold as in FIG. 17A having a preformed retentionstructure placed in the mold configured for injection of a flowablematerial, in accordance with an embodiment;

FIG. 17C shows a mold to make the insert comprising a first componentand a second component, in which the mold comprises a first channel toinject a first flowable material comprising a first therapeutic agentand a second channel to inject a second flowable material comprising asecond therapeutic agent, in accordance with an embodiment;

FIG. 17D shows a mold to make the insert comprising a first componentand a second component, in which the mold comprises a first channel toinject a first flowable material comprising a first therapeutic agentand a second channel to inject a second flowable material comprising asecond therapeutic agent and a third channel to inject a third flowablematerial substantially without therapeutic agent, in accordance with anembodiment;

FIGS. 17E and 17F show a spherical mold having an oval shaped channel tomake the insert in which the mold comprises a first lower componentcomprising a convex spherical surface and a second upper componentcomprising a concave spherical surface to nest with the convex sphericalsurface, in accordance with an embodiment;

FIG. 17G shows a spherical mold having an oval shaped channel to makethe insert in which the mold comprises a first channel to inject a firstflowable material comprising a first therapeutic agent, a second channelto inject a second flowable material comprising a second therapeuticagent and a third channel to inject a flowable material withoutsubstantial therapeutic agent, in accordance with an embodiment;

FIG. 18 shows a manufacturing process, in accordance with an embodiment;

FIG. 18A shows an image of the insert placed on an eye with theretention structure under a fold of conjunctiva, in accordance with anembodiment;

FIG. 18B shows an image of the insert placed on the eye as in FIG. 18Awith the eye looking temporally so as to expose the insert from underthe fold of conjunctiva and such that the retention structure slidesalong the bulbar conjunctiva, in accordance with an embodiment;

FIG. 18C shows an image of the insert placed on an eye with theretention structure extending under a fold of conjunctiva, in accordancewith an embodiment;

FIGS. 19A to 19F show placement locations of the support structurecomprising silicone elastomer coupled to the retention structure asdescribed herein, in accordance with embodiments;

FIG. 20A shows self-loading deflection of an insert, in accordance withan embodiment;

FIG. 21 shows an in situ formed retention structure subsequent toremoval from an eye, in accordance with an embodiment;

FIG. 22 shows a digital image of a human eye measured with a measurementapparatus as described herein, in accordance with an embodiment;

FIG. 23 shows a graph of IOP over time for a patient having an insertplaced on one eye and a control eye for at least about 1 month, inaccordance with an embodiment;

FIG. 24A shows a tested insert comprising a suture and a single 75degree silicone band, in accordance with an embodiment;

FIG. 24B shows a tested insert comprising silicone without a supportingsuture, in accordance with an embodiment;

FIG. 24C shows a tested insert comprising a suture and two opposing 75degree silicone bands, in accordance with an embodiment;

FIG. 24D shows an insert suitable for testing comprising an inner suturecovered with an outer silicone layer along a 360 degree circumference,in accordance with an embodiment;

FIG. 25 shows deformation and curvature of an insert subsequent toplacement in an eye with the insert curved so as to correspond to thecurvature of the lid along the cul-de-sac, in accordance with anembodiment;

FIGS. 26A and 26B show rates of release of a prostaglandin comprisingbimatoprost from a silicone matrix, in which the estimated rate ofrelease for a matrix having 7% a prostaglandin comprising bimatoprostloaded on an insert as described herein is above 3 ug per day for atleast about 120 days, in accordance with an embodiment;

FIG. 27 shows wash time and rates of release of therapeutic agent frommatrices having varying amounts of wash, in accordance with anembodiment;

FIG. 28 shows IOP and rates of therapeutic agent release, in accordancewith an embodiment.

DETAILED DESCRIPTION

Embodiments as described herein can be combined in many ways to provideinserts for placement in the eye for an extended time. The extended timecan depend on the use of the insert and can be at least about one week,for example one month or more. In many embodiments, the insert can beeasily placed in the eye and retained comfortably and continuously foran extended time of at least about two months, for example three months,and in many embodiments six months or more. The insert can be configuredand formed in many ways and may comprise a therapeutic agent for drugdelivery.

The embodiments as described herein can be used in many ways to releasea combination of therapeutic agents simultaneously for an extendingtime. For example, a first therapeutic agent such as a prostaglandin canbe combined with a second therapeutic agent such as a beta blocker. Eachtherapeutic agent may be provided on a segment of the insert. Theprostaglandin may comprise an amount less than the beta blocker, and thesize of the insert segments may correspond to the amount of therapeuticagent. For example, the amount of beta blocker can be from about fivetimes the amount of prostaglandin to about fifty times the amount ofprostaglandin. The beta blocker may be released at a rate substantiallygreater than the rate of the prostaglandin, for example at least aboutfive times the rate of release of the prostaglandin. In manyembodiments, the prostaglandin may comprise one or more of bimatoprost,latanoprost, or travoprost, and the beta blocker may comprise timolol,for example.

The insert can be sized and shaped to fit on the eye in many ways, suchthat when used on a patient population the insert can be easily insertedand provide comfort and retention for at least about 80% of the patientsfor at least about one month, for example comfortably retained for atleast about 3 months for 80% of the patients. In many embodiments, theinsert can be easily inserted and comfortably retained for at leastabout 90% of the patients for at least about one month. In manyembodiments, the insert can be readily inserted by the patient, suchthat the insert can be replaced by the patient, for example replacedmonthly to treat the patient for an extended time of at least aboutthree months. The insert may comprise a unitary shape having asubstantially constant cross-sectional diameter, or a shape having avarying cross sectional diameter, for example.

The therapeutic agent may be placed on the insert at a locationcorresponding to the treatment when placed. For example, when treatinglacrimal gland disease the therapeutic agent can be placed on the insertat a location corresponding to placement near lacrimal gland wheninserted. Alternatively, for glaucoma, the therapeutic agent may belocated on an insert at a location that can provide improved retention,for example a location corresponding to one or more of the upper lid orthe lower lid when placed.

The insert can be configured in many ways and can be configured to movewhen placed on the eye so as to provide improved comfort for thepatient. The insert can be in situ formable or may comprise a shapememory material. In many embodiments, the insert and retention structuremay comprise a material that will retain a shape provided prior toinsertion, for example with molding, such that the insert will returnsubstantially to the pre insertion shape when removed from the eye, forexample one month after insertion. In many embodiments, one or more ofthe insert or the retention structure may comprise a resistance todeflection such that gravity may slightly alter the shape of theretention structure or support when self supporting, such that theretention structure may distort slightly and cannot completely overcomethe distortional force of gravity. In many embodiments the insert maynot comprise enough spring force to overcome friction completely, suchthat the shape may change slightly when placed.

In many embodiments, the insert is configured to move when placed in theeye. The eye can move, for example rotate within the eye socket, and theinsert can move with the conjunctiva of the eye and may slide along theconjunctiva of the eye. In at least some embodiments, the insert can beconfigured to slide when placed in the eye, for example with a lubricouscoating. Alternatively, a portion of the insert can be configured toadhere to the conjunctiva, for example with one or more of a stickytacky surface, a dry hydrogel material or an adhesive.

As used herein the eye encompasses the eyeball and corresponding tissuestructures such as the lids of the eye, the conjunctiva of the eye, andthe lacrimal glands and tear ducts of the eye.

As used herein a conjunctival sac of the eye encompasses a sac of theeye formed with conjunctiva of one of the eyelids and correspondingbulbar conjunctiva.

As used herein like numerals and/or letters can denote like elements inthe drawings as will be apparent to a person of ordinary skill in theart.

FIG. 1A shows an eye 10 suitable for incorporation with the insertapparatus. The eye has a light transmitting cornea 12 and a lighttransmitting lens 21 that form an image on the light sensing retina 26so that the person can see. The eye comprises a light transmittingvitreous humor 27 between the lens 22 and retina 27. The eye 10comprises an axis 10A extending between the cornea 12 and retina 26, andthe axis 10A may comprise one or more known axes of the eye such as thevisual axis, the line of sight, the optical axis, or other axis of theeye. The axis 10A extends an axial distance from cornea 12 to retina 26.The cornea 12 extends to a limbus 14 of the eye, and the limbus connectsto a sclera 24 of the eye. The eye has an iris 18 that may expand andcontract in response to light. The eye also comprises a choroid 28disposed between the sclera 24 and the retina 26. The retina comprisesthe macula 25 for high acuity vision. The eye comprises a pars plana 20located along the scleral portion of the eye near the limbus.

The eye comprises connective tissue structures to protect the eye andallow the eye to move. A pair of lids 40 open to allow the eye to seeand close to protect the eye. An upper lid 42 extends across an upperportion of the eye and a lower lid 44 extends across a lower portion ofthe eye. The eyelids 40 define a palpebral fissure PF extending betweenthe upper lid 42 and lower lid 44. Conjunctiva 50 comprises a loosetissue that protects the eye and allows the eye to move within the bonysocket. The conjunctiva 50 comprises a lid portion comprising palpebralconjunctiva 58 and a globe portion comprising bulbar conjunctiva 56. Thepalpebral conjunctiva 58 lines the inner surface of the upper and lowereyelids that contact the cornea when the eyelids close. The conjunctivaextends from the palpebral conjunctiva 58 of each lid to the bulbarconjunctiva 56 located over the sclera 24 of the eyeball. The bulbarconjunctiva 56 connects to the eyeball near the limbus 14. Theconjunctiva 50 extends from the palpebral conjunctiva 58 of each eyelidand reflects back to form a sac 52 comprising a cul-de-sac 53 and aformix 54. The bulbar conjunctiva 56 is located over the sclera andtranslucent such that the white sclera can be readily seen.

FIG. 1B shows front view of the eye as in FIG. 1A. The pupil 16, iris 18and sclera 24 can be readily seen with a front view of the eye. Themedial canthus MC is located on a nasal end of the palpebral fissure PF,and the lateral canthus LC is located on a lateral end of the palpebralfissure. The human eye comprises a caruncle 59, which is located nasallynear the medial canthus. A fold of the bulbar conjunctiva 56 comprisingthe plica semilunaris can be located near the caruncle 59. As the plicasemilunaris PS can move with the eyeball, the plica semilunaris can movenasally under the caruncle when the patient looks nasal and can becomeincreasingly visible when the patient looks temporally so as to rotatethe plica semilunaris temporally. The eye may comprise additional foldsof the bulbar and palpebral conjunctiva that extend circumferentiallyaround the eye so as to allow the eye to rotate freely within the bonyorbit.

FIG. 1C side sectional view of the conjunctiva of the upper lid 42 andlower lid 44 of the eye as in FIGS. 1A and 1B. The bulbar portion of theconjunctiva 56 comprises a plurality of folds 56F and the palpebralportion of the conjunctiva 50 comprises a plurality of folds 58F. Theconjunctiva 50 reflects back between the bulbar conjunctiva 56 and thepalpebral conjunctiva 58 at the formix 54. The plurality of bulbar folds56F and the plurality of palpebral folds 58F may each extendsubstantially circumferentially around at least a portion of the eye.The sac 52 comprises the cul-de-sac 53, and the cul-de-sac 53 comprisesthe formix 54.

FIG. 1D shows a side sectional view of the upper lid of the eye as inFIGS. 1A to 1C and the folds of the conjunctiva. The bulbar conjunctiva56 of the upper lid 42 has many folds 56F along the conjunctivaextending between the limbus and the formix 54. The palpebralconjunctiva 58 of the upper lid comprises many folds 58F extendingbetween the formix and the lower margin of the upper eyelid 42. Thebulbar conjunctiva 56 of the lower lid 44 has many folds 56F along theconjunctiva extending between the limbus and the formix 54, and thepalpebral conjunctiva 58 of the lower lid 44 comprises many folds 58Fextending between the formix and the upper margin of the lower eyelid44.

The eye can move in many ways, for example with one or more of blinking,squeezing the eye shut, rotation, translation, cyclotorsion, ornystagmus, for example. For example, with rotation of the eye, theconjunctiva may move with the eye in some locations and slide along theeye in other locations. When the eye blinks, the upper lid and lowerlids may slide a substantial distance along eye. In many patients, theeye may exhibit Bell's phenomenon, in which the eyeball may rotateupwards when an attempt is made to close the eyes.

FIG. 1E shows muscles of a pair of eyes that provide cyclotorsion of theeye suitable for combination in accordance with an embodiment asdescribed herein. Cyclotorsion comprises one of many eye movements thatmay occur. The eye comprises many muscles that can be used to rotate theeyeball. Each eyeball is attached to a superior rectus muscle to rotatethe eye superiorly and an inferior rectus muscle to rotate the eyeinferiorly. The lateral rectus muscles rotate the eyeball laterally andthe medial rectus muscles rotate the eye medially. Inferior and superioroblique muscles can cyclo rotate the eye about an axis extendingsubstantially along the optical path of the eye.

Cyclotorsion of the eye can result from viewing of objects near and farto the patient. When the eyes adjust the viewing angle so as to focus onnear or far objects, cyclovergence can occur. The type of the torsionalvergence component can depend systematically on viewing angle elevation.When the eyes fixate on a nearby target, the eyes show in-torsion in upgaze, ex-torsion in down gaze, and no cyclotorsion at some intermediateelevation level. The embodiments described herein can allow slidingmovement of the retention structure along the conjunctiva in response totorsional movement of the eye.

Embodiments similar to FIGS. 1-1-2 to 1-9-1 are shown in PCT App. No.PCT/US2010/037268, published as WO2010/141729 on Dec. 9, 2010, entitled“Anterior Segment Drug Delivery”; and U.S. patent application Ser. No.13/151,001, filed on Jun. 1, 2010, entitled “Anterior Segment DrugDelivery”, the full disclosures of which have been previouslyincorporated herein by reference and are suitable for combination inaccordance with embodiments described herein.

FIG. 1-1-2 shows the lacrimal system 11 which is responsible forproducing and draining the tear fluid. The lacrimal system consists oftwo general areas: first, the lacrimal gland 20, which secretes thetears, and its excretory ducts 22, which transport the fluid to thesurface of the eye and, second, the lacrimal canaliculi 24, the lacrimalsac 26, and the nasolacrimal duct 28, which bring the tear fluid isconveyed into the nose cavity.

FIG. 1-2-1 shows an exemplary embodiment of a therapeutic system 30. Thetherapeutic system 30 comprises an ocular insert 31, and may alsoinclude an insertion device, a configuration altering material thatdissolves (or swells, weakens, tightens, or effects some otheractivation mechanism) to reconfigure the implant from an insertionconfiguration to a deployed configuration, or the like. In alternativeembodiments, activation of the insertion device (or some other tool) mayalso reconfigure the insert from the insertion configuration to thedeployed configuration, or may simply releasably hold the insert in amanner so as to assist insertion. In still further embodiments, theocular insert may not undergo significant changes in shape or otherproperties before, during, or after deployment. Regardless, the ocularinsert is eventually positioned on a region outside an optical zone ofan eye. The ocular insert comprises two structures: a first structure 32and a second structure 34. FIG. 1-2-1 shows the exemplary therapeuticsystem 30 placed outside the optical zone of the eye.

First Structure

The first structure functions as a skeleton which largely holds theimplant in place relative to the structures of the eye, thereby attachesthe implant to the eye, and thus provides support for the secondcushioning structure relative to the anterior portion of the eye. Thisfirst or skeletal structure preferably maintains the attachment of thetherapeutic system to the anterior portion of the eye for at leastthirty days. Should it become medically desirable or should a patient sodesire, the therapeutic system may be removed sooner than the thirtydays; however, from a physical standpoint, it is capable of maintainingthe ocular insert of the anterior surface of the eye for at least thirtydays. In some embodiments, the first structure may continue to helpmaintain the overall implant in the eye for sixty days or more, forninety days or more, or even for 180 days or more, ideally with safe andeffective delivery of therapeutic agents continuing throughout suchimplant periods. Alternative treatment devices and methods may benefitfrom shorter implant periods, optionally for periods of one or moredays, at least a plurality of days, a week or more, two weeks or more,or the like.

Due to its role as skeleton for the insert 31 of therapeutic system 30,the first structure may determine the overall shape of the ocularinsert. The first structure typically comprises a thin metal wire, ahard plastic such as nylon, PMMA, polycarbonate, polyethyleneterepthalate, and/or another polymer, polypropylene or other syntheticsuture material capable of providing the structural support to maintainthe therapeutic system attached to the eye. The first structure may alsocomprise a coated plastic or metal such that the coating contains thetherapeutic medication or provides easier attachment of the second,cushioning element to the skeletal member. The first structure may havea surface treatment such as plasma etching or the like to enable thesecond structure to be suitably attached to the skeletal member.

FIG. 1-2-2 shows a basic embodiment of the first structure. Here thefirst structure 32 is annular or ring-shaped and, has a diameter of atleast 8 mm, and is sized to fit outside the optical zone of the corneaso as not to interfere with patient vision. The annulus of firststructure 32 will preferably comprise a complete ring or toroid, but mayhave some gap along its circumference. The arc angle of the annulus insuch embodiments will be over 180°. FIGS. 1-2-2 and 1-2-3 show a topview and cross-sectional view of the therapeutic system shown in FIG.1-2-2. The therapeutic system can be sized much larger so that the edgesof the structure will lie within the cul-de-sac of the eye. In the casewhere the therapeutic system is intended to be located within thecul-de-sac of the eye, the therapeutic system will desirably be producedin at least two sizes to accommodate varying sizes of eyes (e.g.pediatric versus adult, and optionally different adult eye sizes).Alternative shapes of the first structure may include those of theinserts shown and described in U.S. Pat. No. 3,995,635, the disclosureof which is incorporated herein by reference.

FIG. 1-2-4 shows an embodiment 36 of the therapeutic system 30 where thering comprises two radially outwardly and/or anteriorly extendingprotrusions or bumps 38 on opposed portions of its surface. When the eyeblinks, the lids “trap” the two bumps between the lids and push theocular implant (which otherwise can freely glide on the surface of theeye) back into its therapeutically effective position outside theoptical zone of the cornea.

FIG. 1-2-5 shows an alternative embodiment 30 of the ring-shapedtherapeutic device system 30. In this embodiment, a crescent orbanana-shaped reservoir 62 is attached to the inferior portion of theocular insert.

FIGS. 1-3-1 to 1-3-3 show another embodiment of the therapeutic system30 again including a ring-shaped structure with a diameter of at least 8mm, sized to fit outside the optical zone of the cornea, and also havingtwo or more haptics 66, each radiating from the ring-shaped structureacross to the cul-de-sac of the eye, thus providing an additionalsupport point for the therapeutic system. FIG. 1-3-1 shows thering-shaped therapeutic system with haptics placed on the anteriorstructure of the eye. FIGS. 1-3-2 and 1-3-3 show a top- and across-sectional view, respectively, of ocular insert 64.

FIGS. 1-4-1 to 1-4-2 show an alternate embodiment 68 of the therapeuticsystem 30 in which two or more concentric ring-shaped structures 72 areheld together by four or more haptics 50. The inner ring-shapedstructure has a diameter of at least 8 mm and is sized to fit outsidethe optical zone of the cornea. The next (and subsequent) outerring-shaped structures have progressively larger diameters, theoutermost ring-shaped structure optionally having a diameter of at least12 mm and being sized to fit on the sclera, formix or cul-de-sac of theeye. FIG. 1-4-1 shows the embodiment 68 of the therapeutic system placedon the eye. FIG. 1-4-2 shows the embodiment 68 of the therapeutic systembefore insertion on the eye. The embodiment 68 has the advantage ofproviding a larger surface area for drug delivery, due to the presenceof the two or more rings and four or more haptics. Additional insertshapes having enhanced surface areas may be seen in U.S. Pat. No.4,540,417, the disclosure of which is incorporated by reference. FIG.1-4-3 shows a related embodiment 69 that employs an eccentric designsuch that the one or more ring portions or arc segments 74 are presentin the inferior area of the ring to target delivery to the area of theeye where tears may more readily pool, as in the cul-de-sac. Thiseccentric design may also stabilize the device in a more fixed positionand be less likely to rotate out of position or move into the opticalzone of the eye. In addition, targeting delivery to the cul-de-sac mayenable more effective delivery of some medications to the nasolacrimalsystem in addition to the ocular surface, such as in the case of nasalallergy medications.

In the embodiments described above, the first structure typicallyremains of a constant size and shape, e.g. a ring-shape, or a ring withhaptics that anchor/attach to the sclera, formix or cul-de-sac of theeye.

In other embodiments, the first structure can expand or change shape soas to enhance its attachment to the anterior structure of the eye. FIGS.1-5-1 through 1-5-3 show a serpentine embodiment 76 of therapeuticsystem 30 which shows an expandable ocular insert. FIG. 1-5-1 shows theembodiment 76 inserted on the surface of the eye; FIG. 1-5-2 shows theembodiment 76 before insertion, and FIG. 1-5-3 shows the embodiment inits expanded state. A variety of alternative serpentine configurationsmay be developed or modified so as to take advantage of the cushioningand/or configuration-changing techniques described herein, includingthose of U.S. Pat. No. 4,540,417, the disclosure of which isincorporated herein by reference.

With respect to the already described embodiments, the skeletal membercan be shaped to conform to the radius of curvature of the eye.

The first structure can expand as it absorbs fluid from the tear fluidin the eye or can stretch through a spring action mechanism. Examples ofmaterials that can swell upon insertion in the eye include PVPE, PVA andpolyurethane gels. Examples of materials that may stretch through springaction include platinum alloys, titanium alloys, all stainless steelalloys & tempers, various clad metals and insulated wires. The firststructure may comprise a shape-memory material, such as nitinol, whichwill allow it to change to a desired shape using thermal, magnetic orelectromagnetic activation, from a martensitic to an austenitic state.Other examples of shape memory materials include shape memorypolyurethanes, crosslinked trans-polyoctylene rubber, polynorbornenepolymers, nitinol, polyethylene, PMMA, polyurethane, cross-linkedpolyethylene, cross-linked polyisoprene, polycycloocetene,polycaprolactone, copolymers of (oligo)caprolactone, PLLA, PL/DLAcopolymers, PLLA PGA copolymers, thermoplastic polymers such as PEEK,crosslinked polyethylene terephthalate (PET) and polyethyleneoxide (PEO)block copolymers, block copolymers containing polystyrene andpoly(1,4-butadiene), and other shape memory materials well-known tothose of ordinary skill in the art.

Additional Configurations of the First Structure

FIGS. 1-6-1 and 1-6-2 show another embodiment 78 where the secondcushioning structure comprises two hydrogel scleral contact lenses 80attached to each other, so as to sandwich the first rigid structurebetween them. FIG. 1-6-1 shows the embodiment 78 placed on the surfaceof the eye; FIG. 1-6-2 shows the embodiment 78 before placement. Inembodiment 78, the first structure 82 functions as a skeleton for theocular insert and serves as a drug delivery material. As tear fluidpenetrates the hydrogel lenses, it comes into contact with the firststructure and causes the drug to elute into the tear fluid. Anotherembodiment (not shown) comprises an exoskeletal first structurecomprising a drug delivery material attached to the anterior side of acontact lens. Another embodiment (also not shown) comprises a firststructure comprising a drug delivery material placed on an eye andcovered by a regular, non-drug delivery contact lens to provide acomfortable lid movement.

Second Structure

FIG. 1-7-1 shows a close-up of an exemplary ocular insert 31 of thetherapeutic device system 30 in which the second structure 34 isdisposed throughout the circumferential length of the first structure32. The second structure 34 provides cushioning to facilitate extendedimplantation or wearing of the device, optionally inhibiting irritationto the eye sufficiently to encourage a patient to wear the therapeuticsystem for at least thirty days. The cushioning effect may be achievedat least in part by the material used in the second structure, as wellas by the shape of the surfaces and/or edges of the second structure. Insome embodiments, the second structure may comprise a coating.

The material of the second structure can be soft, biocompatible, andnon-irritant. Examples of such material comprise polymers such ashydrogel or silicone.

Regardless of its overall shape and configuration, edges of the secondstructure are often shaped so as to inhibit friction between them andthe inside portion of the eyelid. FIG. 1-7-2 shows a cross-section of atherapeutic device system comprising a second structure 34 with atapered outer and/or inner edge 84. FIG. 1-7-3 shows a cross-section ofa therapeutic device system comprising a second structure 34 with abeveled edge 86. FIG. 1-7-4 shows a cross-section of a therapeuticdevice system comprising a second structure 34 with a rounded edge 88.FIG. 1-8-1 shows a therapeutic device system 30 with a second structure34 that may have an anterior and/or posterior surface 90 that can beshaped as well to the radius of curvature of the eye 70.

In some embodiments 92 the second, cushioning structure 94 is disposedonly over certain discrete portions along the length of the firststructure 32, desirably at locations where sharper edges or bends mayprovoke irritation to the eye. FIG. 1-9-1 shows the second, cushioningstructure 94 disposed over discrete portions of the length of the firstsupporting structure 32.

In one embodiment, the first and second structure may comprise similarcompositions or materials having differing durometers and/or othercharacteristics, particularly where the material can be processed so asto exhibit the desired properties for both the first and secondstructures.

Drug Delivery Matrix

The drug used in the therapeutic system will often be placed on,embedded, encapsulated or otherwise incorporated into a delivery matrix.The delivery matrix may be included in or on either the first skeletalstructure or the second cushioning structure, or both. The deliverymatrix, in turn, comprises either a biodegradable or a non-biodegradablematerial. The delivery matrix may include, although it is not limitedto, a polymer. Examples of biodegradable polymers include protein,hydrogel, polyglycolic acid (PGA), polylactic acid (PLA), poly(L-lacticacid) (PLLA), poly(L-glycolic acid) (PLGA), polyglycolide,poly-L-lactide, poly-D-lactide, poly(amino acids), polydioxanone,polycaprolactone, polygluconate, polylactic acid-polyethylene oxidecopolymers, modified cellulose, collagen, polyorthoesters,polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(alpha-hydroxyacid), and combinations thereof. Non-biodegradable polymers may comprisesilicone, acrylates, polyethylenes, polyurethane, polyurethane,hydrogel, polyester (e.g., DACRON® from E.I. Du Pont de Nemours andCompany, Wilmington, Del.), polypropylene, polytetrafluoroethylene(PTFE), expanded PTFE (ePTFE), polyether ether ketone (PEEK), nylon,extruded collagen, polymer foam, silicone rubber, polyethyleneterephthalate, ultra high molecular weight polyethylene, polycarbonateurethane, polyurethane, polyimides, stainless steel, nickel-titaniumalloy (e.g., Nitinol), titanium, stainless steel, cobalt-chrome alloy(e.g., ELGILOY® from Elgin Specialty Metals, Elgin, Ill.; CONICHROME®from Carpenter Metals Corp., Wyomissing, Pa.).

To prevent a potential allergic reaction to the ocular insert in apatient, the ocular insert, may comprise a hypoallergenic material.Either or both the first and/or second structure may comprise materialssuch as hydrogels, polyethylene glycol (PEG), or polyethylene oxide(PEO) that prevent adhesion of proteins and thus minimize the chance ofdeveloping an allergic reaction. Alternatively, the drug delivery matrixof the ocular insert may comprise an anti-allergenic and/orantihistaminic compound to prevent an allergic reaction to the ocularinsert. In certain embodiments, the delivery matrix may also includeother materials known in the art.

The embodiments of FIGS. 1-1-2 to 1-9-1 can be combined and modified inmany ways in accordance with the embodiments and teachings as describedherein so as to provide comfortable ocular inserts that can be worn foran extended time and provide therapeutic amounts of therapeutic agentfor the extended time. The first structure as described above maycomprise a retention structure as described herein having a resistanceto inward deflection so as to inhibit expulsion and contact with thecornea. The resistance to inward deflection may comprise a hoopstrength, or spring force, that inhibits contact with the cornea and cangently push the retention structure into the formix of the eye so as tomaintain placement of the insert within the eye, for example. The secondstructure as described above may comprise a support structure asdescribed herein, and the support structure may contain a therapeuticagent. The support structure can be configured in many ways to containthe therapeutic agent and may comprise a soft cushioning matrix of thetherapeutic agent supported with the retention structure, for example.The soft cushioning matrix can be configured to provide substantialamounts of therapeutic agent for an extended time, for example at leastabout 1 ug per day for at least about 1 month and in many embodiments atleast about 3 ug per day for at least about 3 months.

The resistance to deflection to retain the insert may comprise a hoopstrength or spring force, for example, and can be provided in many wayswith many shapes of the first structure comprising the retentionstructure. For example, the insert may comprise a hoop, or ring shapedstructure, and the resistance to deflection may comprise the hoopstrength of the ring shaped structure. The ring shaped structure maycomprise a gap in the ring, for example a “C” shaped ring, and theC-ring may provide a spring force sufficient to resist inward deflectionof the insert toward the cornea and urge the arms of the insert towardthe formix. The insert may comprise a serpentine shaped first structureand second structure, for example as shown above, and the firststructure can be configured to provide the resistance to deflection asdescribed herein.

The second structure can be configured in many ways to providecushioning to facilitate extended implantation or wearing of the device,and can inhibit irritation to the eye sufficiently to encourage apatient to wear the therapeutic system for at least thirty days. Thecushioning second structure may comprise a soft support structureconfigured to contain a therapeutic agent, for example. The cushioningsecond structure may comprise a matrix containing a therapeutic agent,and the matrix may comprise a soft material to support inclusions of atherapeutic agent within the matrix.

The first structure can be pre-formed with a self supporting shape tofit the eye so as to extend away from a plane prior to placement, suchthat the insert comprises a curved shape prior to placement to fit theeye. The insert can be customized to the patient, and may be configuredto the patient based on ethnicity of the patient. Work in relation toembodiments indicates that at least some ethnic populations may comprisea tighter lower lid than other ethnic populations, and that the insertmay be one or more of identified or customized to fit the lower lid ofthe patient.

While the therapeutic agent can be loaded on the insert in many ways, inmany embodiments the first skeletal structure may comprise thetherapeutic agent. For example, the retention structure may comprisestructures to contain the therapeutic agent such as openings, holes, asurface, or other structure to provide the therapeutic agent.

The insert may comprise at least portion configured to inhibit mucousformation, and the at least a portion can be configured for placementnear the medial canthus where mucous can accumulate in the eye. The atleast a portion may comprise one or more of a cross-sectional size of atleast about one half of one mm, a lubricous coating, or combinationsthereof, for example. The at least a portion may comprise the secondcushioning structure, for example.

FIG. 2A shows an insert 100 for insertion into an eye. The insert 100comprises a retention structure 110 and a support structure 120 toprovide benefit to the wearer. The support structure 120 may comprise afirst inclined surface of first tapered end portion 122 and a secondinclined surface of second tapered end portion 124, so as to allow thesupport structure 120 to slide within the conjunctival sac of the eye.The first inclined surface of first tapered end portion 122 may comprisea curved surface 122C to couple the first inclined surface of firsttapered end portion 122 to the generally elongate surface of the supportstructure that can be cylindrical. The first and second inclinedsurfaces can be configured in many ways and may comprise crescent,torpedo or other shapes so as to contact the conjunctiva within the sacand allow movement of the insert. The second inclined surface of secondtapered end portion 124 may comprise a curved surface 124C to couple thesecond inclined surface of second tapered end portion 124 to thegenerally cylindrical surface of the support structure. The firstinclined surface of first tapered end portion 122 and the secondinclined surface of second tapered end portion 124 can decrease pressureto the conjunctiva when the support structure 120 is placed in the sacof the conjunctiva, and may encourage movement of the support structure120 within the conjunctival sac, for example when the eye moves.

The retention structure can be sized to the eye in many ways and maycomprise a dimension across 114A such as a diameter corresponding to amaximum diameter of the eye transverse to the optical path of the eye.The retention structure may comprise a diameter slightly larger than themaximum diameter of the eye transverse to the optical path, a diameterslightly smaller than the maximum diameter of the eye transverse to theoptical path, or a diameter approximately equal to the maximum diameterof the eye transverse to the optical path. For example, the eye maycomprise a maximum diameter of about 24 mm transverse to the axiallength of the eye, and the dimension 114A of the retention structure canbe slightly larger than the diameter of the eye, for example a diameterof about 25 mm. The dimension 114A of the retention structure can bedetermined based on a measurement of the patient such as a measurementof the eye as described herein, or based on fitting one or more of aplurality of retentions structure to the eye as described herein, orcombinations thereof, for example.

The support structure 120 may comprise a container, for example. Thecontainer may comprise a drug reservoir containing a therapeutic agent130 and release therapeutic amounts of the therapeutic agent for anextended time. Alternatively or in combination, the support structure120 may comprise a matrix 140 supporting inclusions of a therapeuticagent 130 to release therapeutic amounts of the therapeutic agent for anextended time. The inclusions of the therapeutic agent may comprise oneor more of particles, droplets, or crystals of the therapeutic agent.

In many embodiments support structure 120 comprises the matrix 130having a surface area sized to release therapeutic amounts of thetherapeutic agent for the extended time. The surface area of the matrixto release the therapeutic agent may comprise an exposed surface area,or a surface area at least partially covered with a non-matrix material,such as a lubricous coating, for example a hydrogel. The area of thematrix to release the therapeutic agent may correspond to a distance 126of the support structure 120 and a cross sectional dimension 127 such asa diameter across the support structure 120. The rate of release of thetherapeutic agent can be determined by one or more of a solubility ofthe therapeutic agent in the matrix material, the surface area of thematrix material, or the solubility of the therapeutic agent in the tearliquid of the eye. The therapeutic agent may comprise an amount of oneor more of the therapeutic agents as described herein and the matrixmaterial may comprise one or more of the matrix materials as describedherein. For example, the matrix material may comprise silicone and thetherapeutic agent may comprise inclusions of a prostaglandin such asbimatoprost crystals or latanoprost droplets.

The distance 126 can be sized such that the support structure 120encompasses the whole of the retention structure 110, i.e., correspondsto 360 degrees around the retention structure, or may be less than 360degrees, for example, it may encompass 270 degrees or 180 degrees. Thedistance 126 can be sized such that the support structure 120 can fitsubstantially within at least a portion of one or more of theconjunctival sacs as described herein. The distance 126 may correspondto no more than about 90 degrees around retention structure 110, forexample. In many embodiments, the distance 126 corresponds to no morethan about 80 degrees so as to fit within the inferior temporal portionof the conjunctival sac, for example no more than about 75 degrees.Alternatively or in combination, the distance 126 can be sized to fitwithin the inferior conjunctival sac of the eye, for example. Thecross-sectional dimension 127 can be within a range from about 0.1 mm toabout 3 mm across, for example within a range from about 0.5 to 2 mmacross, for example.

The distance 126 and dimension 127 can be sized to have a volumecorresponding to an appropriate amount of therapeutic agent. Forexample, the amount of therapeutic agent contained on support structure120 can be within a range from about 1 ug to about 10,000 ug. Forexample, the support structure 120 can be approximately 10 mm long andhave a cross sectional dimension of about 1 mm so as to comprise avolume of about 30 uL corresponding to a mass of about 30 mg. For a 30%loading of the therapeutic agent in the matrix, the corresponding amountof therapeutic agent is about 10,000 ug, and the amount of therapeuticagent can be increased or decreased based on the dimensions of supportstructure 120. For example, the amount of therapeutic agent can exceed10,000 ug.

Table 1 shows examples of therapeutic agent 130 suitable for use withretention structure 110. The therapeutic agent 130 can be used in manyways, and may comprise one or more of many therapeutic agents deliveredin one or more of many ways as described herein. The therapeutic agent130 may comprise a component of retention structure 110, for exampleinclusions within a material of retention structure 110. Alternativelyor in combination, retention structure 110 can be supported with supportstructure 120 such that support structure 120 contains the therapeuticagent 130 for release for an extended time as described herein.

TABLE 1 Examples of Indications and Therapeutic Agents IndicationTherapeutic Agent Glaucoma Prostaglandin or (Prostaglandin) analog (e.g.Bimatoprost or Latanoprost) Glaucoma Bimatoprost + (Prostaglandin orCarbonic analog + second Anhydrase drug, e.g. Inhibitor (CAI)latanoprost or (dorzolamide) bimatoprost) Glaucoma Prostaglandin(Canine) (e.g. Bimatoprost or Latanoprost) Corneal steroid Transplant,Prevention of Rejection Bacterial One or more Conjunctivitis newerantibiotics that have little resistance built up Therapeutic AgentCandidates Dry Eye Cyclosporine steroid (e.g.— Loteprednol,Fluoromethalone) Non-penetrating steroid (e.g. free acid of steroid)Doxycycline or azithromycin Non-pharmacologic agent (e.g. lipid) Fattyalcohol (for example cetyl alcohol or stearyl alcohol) Fatty acid, forexample long chain fatty acid Oil Post-Cataract Antibiotic + Steroid;Surgery (NSAID optional) Post-Laser Antibiotic + Steroid; Surgery (NSAIDoptional) Allergy Olopatadine Trachoma Doxycycline or other antibioticBlepharitis Tetracycline, Doxycycline, Azithromycin, or other antibioticNon-pharmacologic agent (e.g. lipid) Fatty alcohol (lipid cetyl alcohol)Fatty acid, for example long chain fatty acid Oil (e.g. silicone oil)

Alternatively or in combination with the therapeutic agents in Table 2,the therapeutic agent 130 may comprise one or more of the following:anti-glaucoma medications, (e.g. adrenergic agonists, adrenergicantagonists (beta blockers), carbonic anhydrase inhibitors (CAIs,systemic and topical), parasympathomimetics, prostaglandins andhypotensive lipids, and combinations thereof), antimicrobial agent(e.g., antibiotic, antiviral, antiparacytic, antifungal, etc.), acorticosteroid or other anti-inflammatory (e.g., an NSAID), adecongestant (e.g., vasoconstrictor), an agent that prevents of modifiesan allergic response (e.g., an antihistamine, cytokine inhibitor,leucotriene inhibitor, IgE inhibitor, immunomodulator), a mast cellstabilizer, cycloplegic or the like. Examples of conditions that may betreated with the therapeutic agent(s) include but are not limited toglaucoma, pre and post surgical treatments, dry eye and allergies. Insome embodiments, the therapeutic agent may comprise a lubricant or asurfactant, for example a lubricant to treat dry eye.

The therapeutic agent may comprise a prostaglandin analog suitable fortreatment of glaucoma as described herein. The prostaglandin analog forthe treatment of glaucoma may comprise one or more of latanoprost,bimatoprost, unoprostone or travoprost, for example.

The therapeutic agent 130 may comprise one or more of the following ortheir equivalents, derivatives or analogs: thrombin inhibitors;antithrombogenic agents; thrombolytic agents; fibrinolytic agents;vasospasm inhibitors; vasodilators; antihypertensive agents;antimicrobial agents, such as antibiotics (such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin,tobramycin, gentamycin, erythromycin, penicillin, sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole,nitrofurazone, sodium propionate), antifungals (such as amphotericin Band miconazole), and antivirals (such as idoxuridine trifluorothymidine,acyclovir, gancyclovir, interferon); inhibitors of surface glycoproteinreceptors; antiplatelet agents; antimitotics; microtubule inhibitors;anti-secretory agents; active inhibitors; remodeling inhibitors;antisense nucleotides; anti-metabolites; antiproliferatives (includingantiangiogenesis agents); anticancer chemotherapeutic agents;anti-inflammatories (such as hydrocortisone, hydrocortisone acetate,dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone,prednisolone 21-phosphate, prednisolone acetate, fluoromethalone,betamethasone, triamcinolone, triamcinolone acetonide); non steroidalanti-inflammatories (NSAIDs) (such as salicylate, indomethacin,ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen,naxopren, piroxicam and nabumetone). Such anti inflammatory steroidscontemplated for use in the methodology of the embodiments describedhere, include triamcinolone acetonide (generic name) and corticosteroidsthat include, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, flumetholone, and derivatives thereof);antiallergenics (such as sodium chromoglycate, antazoline,methapyriline, chlorpheniramine, cetrizine, pyrilamine,prophenpyridamine); anti proliferative agents (such as 1,3-cis retinoicacid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin);decongestants (such as phenylephrine, naphazoline, tetrahydrazoline);miotics and anti-cholinesterase (such as pilocarpine, salicylate,carbachol, acetylcholine chloride, physostigmine, eserine, diisopropylfluorophosphate, phospholine iodine, demecarium bromide);antineoplastics (such as carmustine, cisplatin, fluorouracil3;immunological drugs (such as vaccines and immune stimulants); hormonalagents (such as estrogens,—estradiol, progestational, progesterone,insulin, calcitonin, parathyroid hormone, peptide and vasopressinhypothalamus releasing factor); immunosuppressive agents, growth hormoneantagonists, growth factors (such as epidermal growth factor, fibroblastgrowth factor, platelet derived growth factor, transforming growthfactor beta, somatotrapin, fibronectin); inhibitors of angiogenesis(such as angiostatin, anecortave acetate, thrombospondin, anti-VEGFantibody); dopamine agonists; radiotherapeutic agents; peptides;proteins; enzymes; extracellular matrix; components; ACE inhibitors;free radical scavengers; chelators; antioxidants; anti polymerases;photodynamic therapy agents; gene therapy agents; and other therapeuticagents such as prostaglandins, antiprostaglandins, prostaglandinprecursors, including antiglaucoma drugs including beta-blockers such asTimolol, betaxolol, levobunolol, atenolol, and prostaglandin analoguessuch as bimatoprost, travoprost, Latanoprost etc; carbonic anhydraseinhibitors such as acetazolamide, dorzolamide, brinzolamide,methazolamide, dichlorphenamide, diamox; and neuroprotectants such aslubezole, nimodipine and related compounds; and parasympathomimetricssuch as pilocarpine, carbachol, physostigmine and the like.

FIG. 2B shows a cross sectional view of retention structure 110. Theretention structure 110 comprises a maximum dimension across 112 such asa diameter. The retention structure 110 can be shaped in many ways andmay comprise an oval cross section or other non-circular cross sectionalshape. The maximum dimension across retention structure 110 maygenerally comprise less than about 2 mm, for example 1 mm or less (e.g.0.75 mm or less), such that the retention structure can fit within theone or more folds of the conjunctiva such as one or more folds of thebulbar conjunctiva extending between the limbus and the formix, or theone or more folds of the palpebral conjunctiva extending between theeyelid margin and the formix. Work in relation to embodiments asdescribed herein suggests that a maximum cross sectional dimension of nomore than about 1.0 mm can allow the retention structure to fitcomfortably within the one or more folds of the conjunctiva away fromthe formix, for example.

The retention structure 110 comprises a material and cross sectionalsize to fit within one or more folds of the conjunctiva and to allowdeflection of the retention structure with at least some resistance todeflection so as to inhibit inward movement of the retention structure110 to the cornea. Table 1A lists non-limiting examples of suture sizesand materials that can be used to provide retention structure 110. Inmany embodiments, the support structure 120 can be molded over thepreformed retention structure 110 as described herein. Alternatively orin combination, the retention structure may comprise a molded structure,for example a molded material having hardness sufficient to provide thedeflection with at least some resistance. For example, retentionstructure 110 may comprise a molded elastic material such as silicone orrubber having a hardness, so as to provide the resistance to deflection.

TABLE 1A Suture Sizes and Structures Suitable for the RetentionStructure. Synthetic Non- Polypropylene Nylon Self- Resistance toCollagen Absorbable Absorbable American Self-Loading Loading DeflectionU.S.P. Diameter Diameter Diameter Wire Deflection Deflection(Polypropylene Designation (mm) (mm) (mm) Gauge (degrees) (degrees) Nper mm) 6-0 0.1 0.070 0.070 38-40 5-0 0.15 0.1 0.1 35-38 17 17 4-0 0.20.15 0.15 32-34 12 12 0.1 3-0 0.3 0.2 0.2 29-32 12 8 2-0 0.35 0.3 0.3 280 0.4 0.35 0.35 26-27 1 0.5 0.4 0.4 25-26

The retention structure 110 may comprise an erodible material or anon-erodible material. Alternatively or in combination, the matrixmaterial may comprise an erodible material. The material of theretention structure can be configured to erode such that the retentionstructure erodes at a rate corresponding to release of the therapeuticagent and no longer retains the support structure 120 comprising thetherapeutic agent 130 when a dose of the therapeutic agent has beendelivered for an extended time. This erosion of the retention structurecan indicate to the patient that the therapeutic agent has beendelivered and a new insert may be appropriate. Alternatively, theerosion of the retention structure can indicate completion of thetreatment. For example, with post surgical placement of the insert, theretention structure of the insert can be configured to erode afterseveral days, for example at about one week, so as to indicatecompletion of the prescribed treatment. Alternatively, the erodiblematrix may erode at a rate faster than a rate of the erodible retentionstructure such the matrix is retained in the eye and erodes before theretention structure.

The insert 100 can be configured in many ways to indicate a condition ofthe insert to a patient or a treating physician, for example to indicatethat one or more of removal or replacement of the insert may beappropriate. For example, the support structure can be configured tochange color from a first color to a second color when the supportstructure has been placed in the eye for an amount of time. The supportstructure can be configured to change volume from a first amount to asecond amount, in which a difference between the first amount and thesecond corresponds to an amount of time the support structure has beenplaced on the eye.

FIG. 2C shows an insert as in FIGS. 2A and 2B deflected in response toplacement in an eye and corresponding force to urge the retentionstructure outward. Placement of the retention structure within thesuperior and inferior sacs of the conjunctiva of the eye can result inat least some deflection of the retention structure. For example, theretention structure can be deflected inwardly between the upper andlower lids so as to comprise a second configuration when placed in theeye comprising a first dimension across 114B and a second dimensionacross 114C corresponding to an oval or elliptical shape of theretention structure 110.

FIG. 2C1 shows a retention structure 110 self-loaded and deflected at anangle 110SLA. The retention structure may comprise a self-loadingresistance to deflection, such that the retention structure 110 deflectsto angle 110SLA when one end is supported and held in place and theweight of the intermediate portion 110I and opposite portion deflect theretention structure. The insert comprising retention structure 110 andsupport structure 120 can be measured similarly. Alternatively, theinsert 100 can be measured without the retention structure 110 when theinsert 100 does not comprise retention structure 110, for example. Theretention structure may comprise an upper portion 110U comprising thesupported end, and an intermediate portion 110I and a lower portion 110Lsupported with the end, for example.

FIG. 2C2 shows torsional force 110T of a retention structure 110 at afirst location and resistance to twisting about an axis 110TA. The firstlocation may comprise an upper portion 110U, for example, or a lowerportion 110L, for example. The first location of the retention structureretention structure 110 may extend through a cross-section of theretention structure 110 comprising axis 110TA, for example. When the eyeblinks, the force of the lid can engage a portion of the retentionstructure so as to provide torsional force 110T to the retentionstructure, and the retention structure can resist twisting of theretention structure. The resistance to self-loading deflection of theretention structure as described herein may correspond to the resistanceto torsional deflection and the weight of the retention structure, forexample.

The retention structure 110 can be deflectable and can be configured inmany ways with a resistance to deflection, so as to inhibit deflectionof the retention structure. The resistance to deflection may comprise aresistance to inward deflection, so as to inhibit inward deflection ofthe retention structure toward the cornea. The resistance to deflectionmay comprise a resistance to self-loading deflection, and theself-loading resistance to deflection may correspond to an angle ofdeflection when one end retention structure is held horizontally and theopposite end and intermediate portion of the retention structure deflectdownward at an angle away from horizontal in response to gravityloading. The resistance to deflection may comprise a torsionalresistance to deflection, for example, such that rotation of theretention structure about an axis extending through a cross-sectionaldiameter is inhibited, for example such that twisting of the retentionstructure along the portion is inhibited. The resistance to deflectionmay correspond to an inward pressure from the upper and lower formices,and the resistance to deflection can be sufficient to inhibit contactwith the cornea, for example when the eye blinks. Alternatively or incombination, the resistance to deflection may correspond to resistanceto torsional rotation a portion of the retention structure under a lidsuch that the amount torsional rotation is inhibited. For example, whenthe upper lid blinks, the upper portion of the insert under the upperlid may resist rotation about an axis extending through a cross-sectionof the portion of retention structure under the upper lid. When theretention structure comprises a formed 3-D shape profile, the retentionstructure may comprise a resistance to deflection away from the formed3-D shape profile toward a plane.

The resistance to deflection of the retention structure sufficient toinhibit contact with the cornea may correspond to a self-loadingresistance to deflection, and the self-loading deflection angle can bewithin a range from about 0 degrees (i.e. rigid) to about 60 degrees,for example. In many embodiments, the retention structure can deflect atleast about a degree so as to facilitate placement in the eye and allowthe retention structure 110 to deflect when sliding and rotating alongthe conjunctival sacs about the axial length of the eye withcyclotorsion of the eye as described herein.

The resistance to inward deflection of the retention structure can besufficient to inhibit contact with the cornea and can be within a rangefrom about 0.01 N per mm to about 1 N per mm of inward deflection alongdimension 114B, so as to allow the retention structure 110 to slide androtate along the conjunctival sacs about the axial length of the eyewith cyclotorsion of the eye and place the support structure 120 alongthe inferior temporal location of the conjunctival sac as describedherein.

The retention structure 110 may comprise one or more of many materials,for example one or more materials of the first structure 32 as describedherein. The material of retention structure 110 may comprise one or moreof a metal, stainless steel, a wire, stainless steel wire, a shapememory material, a shape memory metal, Nitinol, a shape memory plastic,polypropylene, nylon, a thermoset polymer, a thermoset plastic or otherpreformed memory material for example. The retention structure 110 canbe preformed with a shape as described herein corresponding to a shapeof the eye. Alternatively or in combination, the retention structure 110may comprise an in situ shape forming material that conforms to theshape of the conjunctiva of the eye and retains the formed shapecorresponding to the conjunctiva, so as to provide a resistance todeflection away from the shape formed in situ. For example, theretention structure may comprise a circular shape prior to placement andform an oval shape when placed in the eye, and the retention structuremay retain the oval shape when placed in the eye for a sufficient timesuch that the retention structure resists deflection away from the ovalshape. The in situ shape forming material may comprise one or more ofmany materials such as polypropylene or nylon, for example.

The retention structure can be configured in many ways to provide thestiffness and resistance to deflection as described herein so as toprovide comfort and retention of the insert. The resistance todeflection may comprise one or more of self-supporting resistance todeflection, an inward resistance to deflection, or a hoop strength ofthe retention structure, or combinations thereof, for example.

Table 1B shows examples of values of angles in degrees corresponding tothe self-loading resistance to deflection that can be obtained inaccordance with the teachings and embodiments described herein. Theretention structure 110 may comprise a self-loading resistance todeflection so as to provide a self-loading deflection angle within arange from about 0 degrees to about 70 degrees, and one or more of manyvalues within theses ranges for example. The self-loading deflectionangle can be measured by holding one end of the insert horizontal andmeasuring deflection of the intermediate portion and opposing endrelative to horizontal as described herein. Table 1B providesnon-limiting examples, and the self-loading deflection angle can belower, or greater, for example, and may vary with the cross sectionaldiameter of the retention structure so as to provide increased stiffnesscorresponding to increased surface area of the portion of the insertengaging the conjunctiva. The self-loading resistance to deflection ofone of the examples of Table 1B can be combined with the self-loadingresistance to deflection of another example of Table 1B so as to definethe range. For example, the range can be from about 1 degree (Example 2of Table 1B) to about 60 degrees (Example 21 of Table 1B). The retentionstructure may comprise one or more of a material, a dimension, or ashape so as to provide the self-loading resistance to deflection andcorresponding deflection angle as described herein. Based on theteachings described herein, a person of ordinary skill in the art canconduct experiments so as to determine empirically the deflection angleand self-loading resistance to deflection of retention structure 110 soas to provide movement of the insert and retention structure on theconjunctiva and to inhibit contact with the cornea.

TABLE 1B Self-Loading Deflection Angle of Retention Structure (degrees)Angle Example (degrees) 1 0 2 1 3 2 4 3 5 4 6 5 7 6 8 7 9 8 10 9 11 1012 15 13 20 14 25 15 30 16 35 17 40 18 45 19 50 20 55 21 60 22 65 23 70

Table 1C shows examples of values of resistance to deflection in N permm that can be obtained in accordance with the teachings and embodimentsdescribed herein. The retention structure 110 may comprise a resistanceto deflection within a range from about 0.005 N/mm to about 10 N/mm, forexample within a range from about 0.01 N per mm of deflection to about 1N per mm of deflection, and one or more of many values within thesesranges for example. Table 1C provides non-limiting examples, and theresistance to deflection can be lower, or greater, for example, and mayvary with the cross sectional diameter of the retention structure so asto provide increased stiffness corresponding to increased surface areaof the portion of the insert engaging the conjunctiva. The resistance todeflection of one of the examples of Table 1C can be combined with theresistance to deflection of another example of Table 1C so as to definethe range. For example, the range can be from about 0.05 N per mm(Example 5 of Table 1C) to about 0.5 N per mm (Example 14 of Table 1C).The retention structure may comprise one or more of a material or shapeso as to provide the resistance to deflection as described herein. Basedon the teachings described herein, a person of ordinary skill in the artcan conduct experiments so as to determine empirically the resistance todeflection of retention structure 110 to provide movement of the insertand retention structure on the conjunctiva and to inhibit contact withthe cornea.

TABLE 1C Resistance to Deflection of Retention Structure (N/mm) ExampleResistance 1 0.01 2 0.02 3 0.03 4 0.04 5 0.05 6 0.06 7 0.07 8 0.08 90.09 10 0.1 11 0.2 12 0.3 13 0.4 14 0.5 15 0.6 16 0.7 17 0.8 18 0.9 19 120 0.005 21 0.006 22 0.007 23 0.008 24 0.009 25 1.2 26 1.5 27 2 28 5 2910

The retention structure can be configured in many ways to provide theresistance to deflection and to fit within one or more of the folds ofconjunctiva as described herein. Table 1D list examples of maximum crosssectional dimensions, for example diameters, of retention structures inaccordance with embodiments. The diameter of the retention structure canbe within a range from about 0.05 mm to about 2 mm, for example, and oneor more of many values within the range for example. The diameter of oneof the examples of Table 1C can be combined with the diameter of anotherexample of Table 1C so as to define the range. For example, the rangecan be from about 0.1 mm (Example 10) to about 0.5 mm (Example 14).Based on the teachings described herein, a person of ordinary skill inthe art can conduct experiments so as to determine empirically themaximum dimension across retention structure 110 so as to fit theretention structure 110 within the one or more folds of conjunctiva asdescribed herein and to provide movement of the insert and retentionstructure on the conjunctiva and so as to inhibit contact with thecornea.

TABLE 1D Cross-sectional Diameters of retention structures (mm) ExampleDiameter 1 0.05 2 0.1 3 0.2 4 0.3 5 0.4 6 0.5 7 0.6 8 0.7 9 0.8 10 0.911 1 12 1.2 13 1.5 14 1.7 15 2

The examples of Table 1D can be combined in many ways with the examplesof Tables 1A, 1B and 1C so as to provide the retention structure 110having the resistance to deflection to inhibit contact with the corneaand cross sectional dimension to fit within one or more folds of theconjunctiva as described herein, and the ranges of Table 1C can becombined with the ranges of Table 1D, for example.

The retention structure may comprise a three dimensional profilecorresponding to the eye of the patient, such that the retentionstructure extends away from a plane when free standing, for example whenplaced on a flat surface. The examples of Tables 1A, 1B, 1C, and 1D canbe combined with the preformed shape to provide a resistance todeflection such that the retention structure extends away from a planewhen placed on a flat surface and urges the portion of the retentionstructure placed under the lower lid toward the eyeball when the firstportion of the retention structure is placed under the upper lid. Workin relation to embodiments also suggests that one or more of theresistance to deflection or the column strength can provide sufficientforce so as to transmit circumferential torsional force from a firstportion of the structure to a second portion of the structure, such thatthe first portion of the structure can urge the second portion of thestructure. For example, the first portion comprising at least a portionof support structure 120 may urge a second portion comprising at least aportion retention structure 110 circumferentially around the pupil ofthe eye with cyclotorsion of the eye. The retention structure 110 maycomprise a molded preformed retention structure, for example a moldedsilicone elastomer having the three dimensional oval shape correspondingto the bulbar conjunctiva of the eye of the patient, and the threedimensional molded shape may comprise a resistance to deflection towarda plane similar to the sutures of Table 1C. For example, work inrelation to embodiments suggests that silicone elastomer having across-sectional diameter of within a range from about 0.5 mm to about1.0 mm may have a resistance to deflection similar to a polypropylenesuture having a cross-sectional diameter within a range from about 0.1mm to about 0.2 mm.

FIG. 2D shows an insert having a preformed oval shape extending along aconvex surface of an eye, such that the ring extends away from a planeand resists deflection toward a plane. The insert can be configured todeflect away from a plane in many ways and can be bent at one or morelocations so as to extend away from the plane, or may comprise one ormore curved portions extending away from the plane with curvaturecorresponding to the eye so as to fit the eye of the patient with theone or more curved portions, or combinations thereof. The plane maycorrespond to a plane of the limbus 14. The convex surface of the eyemay comprise one or more of a spherical surface, a toric surface, anelliptical surface, a cylindrical surface, a conical surface, orcombinations thereof, corresponding to one or more of the scleralsurface or the bulbar conjunctival surface of the eye of patient. Theinsert 100 may comprise a three dimensional shape (hereinafter “3D”)corresponding substantially to the shape of the insert when placed onthe eye. The pre-formed shape of retention structure 110 prior toplacement on the eye may comprise a substantially oval shape having anelevation profile corresponding to the oval shape placed on a sphericalsurface corresponding to the eyeball of the patient. The substantiallyoval preformed shape may comprise a first maximum dimension across 114A1in a first direction corresponding to a superior-inferior directionalong the eyeball of the patient and a second maximum dimension across114A2 along a second direction corresponding to a nasal-temporaldirection along the eyeball of the patient. The first maximum dimensionacross 114A1 may correspond to a minor axis of an ellipse and the seconddimension across 114A2 may correspond to a major axis of an ellipse,although the generally oval shape may comprise one or more of manyshapes such as lentoid, conic cross section, elliptical or other shapeprojected onto a spherical surface as described herein. The insert 100may extend closer to the limbus 14 in along the superior and inferiorportions than the nasal and temporal portions. As the eyeball maycorrespond to a substantially spherical surface, the eyeball maycomprise a radius of curvature Rb corresponding to the spherical shapeof the eyeball. Consequently, the nasal and temporal portions of theinsert may extend away from a plane corresponding to the inferior andsuperior portions of the insert.

FIG. 2E shows a side view of an insert as in FIG. 2D extending alongnasal-temporal and anterior posterior directions. The anterior directionA, the posterior direction P, the nasal direction N, and the temporaldirection T are each shown. The insert may comprise a preformed 3D shapecorresponding to the radius Rb and the first dimension across 114A1 andthe second dimension across 114A2, such that the lower portion of theinsert is urged posteriorly toward the bulbar conjunctiva when the upperlid covers at least a portion of the insert. Alternatively or incombination, the insert may comprise a preformed 3D shape correspondingto the radius Rb and the first dimension across 114A1 and the seconddimension across 114A2, such that the lower portion of the insertresists deflection anteriorly away the bulbar conjunctiva when the upperlid covers at least a portion of the insert. This resistance todeflection can be provided with the insert preformed with the 3D profilecorresponding to the radius Rb of the patient. The limbus 14 maycorrespond to a plane of the eye. The retention structure 110 maycomprise a first preformed sag height 114S1 corresponding to ananterior-posterior elevation distance from the limbus to the inferiorand superior portions of the insert. The retention structure 110 maycomprise a second preformed sag height 114S2 corresponding to ananterior posterior elevation distance from the limbus to the nasal andtemporal portions of the insert. The difference in the sag heights maycomprise a differential sag height 114DS and the differential sag height114DS may correspond to an amount the retention structure deflects froma plane when the insert is placed on a flat surface. The supportstructure 120 can be shaped similarly to the retention structure 110,such that the insert 100 comprises the three dimensional shapecorresponding to the eye of the patient. The retention structure 110 maycomprise one or more of many shapes as described herein, and thecorresponding sag height profile extending around the insert can bedetermined based on the projection of the shape onto a spherical surfacehaving radius Rb corresponding to the eye of the patient. The retentionstructure 110 and the support structure 120 comprising the threedimensional shape profiles may comprise the resistance to deflection asdescribed herein.

The insert 100 comprising the retention structure having the 3D shapeprofile may comprise a surface to retain the insert. The surface may beconfigured in one or more of many ways to retain the insert. The surfacemay comprise a sticky, tacky surface to retain the insert within the oneor more folds of the conjunctiva. The sticky, tacky surface may comprisea soft hydrophilic surface, such as the surface of a soft siliconeelastomer. Alternatively or in combination, the surface may comprise acoating of hydrogel material as described herein, for example asubstantially dry hydrogel material such that the dry hydrogel materialmay stick to the one or more folds when placed and moisture drawn fromthe tissue or mucus contacting the hydrogel. For example, the hydrogelcoating may extend along a portion of the insert corresponding to thelacrimal gland. Alternatively, the insert may comprise a lubricouscoating to encourage movement of the insert with the eye, such that the3D shape profile can slide along the conjunctiva and resist deformationwhen the eye moves. For example, the lubricous coating can be placedover the insert at locations corresponding to one or more of thelacrimal gland or the caruncle. The insert 100 comprising the 3Dshape/profile as described herein may provide retention whensubstantially the entire surface of the insert 100 comprising theretention structure 110 and the support structure 120 are each coatedwith the lubricous coating as described herein, such that the insert 100can slide along the sacs of the conjunctiva and seat the insert withmovement of the insert along the conjunctiva. For example, the insert100 may be dip-coated in a hydrogel, and the hydrogel can be moist so asto provide the lubricous coating and resist deflection of the insertaway from the inferior bulbar conjunctiva with the 3D shape profile asdescribed herein.

FIG. 2F shows a side view of an insert as in FIG. 2D extending alongsuperior-inferior and anterior-posterior directions. The anteriordirection A, the posterior direction P, the superior direction S, andthe inferior direction I are each shown, along with the correspondingsag heights.

FIG. 2G shows an insert having a preformed oval shape extending along aspherical surface and in which the oval ring has a first portioncorresponding to the upper conjunctival sac and a second portioncorresponding to the lower conjunctival sac and thinner than the secondportion, such that the ring extends away from a plane and resistsdeflection toward a plane and urges the lower portion toward theinferior bulbar conjunctiva when the first portion is retained with theupper lid. The insert 100 may comprise a portion placed under the upperlid having a cross sectional size 113 greater than a portion of theinsert placed under the lower lid having a cross sectional size 112. Thethicker portion placed under the upper lid can be retained at leastpartially with the pressure of the lid, and the 3D shape profile of theinsert can resist deflection of the lower portion away from the bulbarconjunctiva. The portion comprising the cross sectional size 113 maycontain one or more therapeutic agents and matrices to contain thetherapeutic agent such as a silicone matrix comprising inclusions of atherapeutic agent, and the portion comprising the cross sectional size112 may comprise the retention structure 110 such as the suture ormolded silicone ring segment as described herein.

FIG. 2H shows an insert 100 comprising a support structure 120 and aretention structure 110 having a preformed oval shape extending along aconvex spherical surface, such that the insert extends away from a planeand resists deflection toward the plane. The insert is shown as seenfrom the front of the patient so as to extend along nasal/temporal andanterior/posterior directions.

FIG. 2I shows a top view of the insert 100 as in FIG. 2H extending alongnasal-temporal and anterior posterior directions. The shape of thepre-formed insert 100 corresponds to the shape of inserts that have beenin situ formed within the eye as described herein.

In many embodiments, the pre-formed shape of the insert 100 isdetermined substantially by the retention structure 110 that is coveredwith the support structure 120 comprising matrix 140 containingtherapeutic agent 130 as described herein. Alternatively, the supportstructure 120 as described herein can be configured with sufficientstiffness so as to provide the preformed three-dimensional shape providesuch that the insert can be provided without the retention structure.The upper (superior) portion of the insert 100 comprises a curvature115C1 so that the insert bends posteriorly and toward the eye. The lower(inferior) portion of the insert 100 comprises a curvature 115C2 so thatthe insert bends posteriorly and toward the eye. The intermediate nasalportion of the insert 100 comprises a curvature 115C3 so that the insertbends anteriorly and away from the eye. The intermediate nasal portionof the insert 100 comprises a curvature 115C4 so that the insert bendsanteriorly and away from the eye.

FIG. 2J shows an insert 100 comprising a retention structure 110 havinga preformed curved annular shape corresponding to the eyelid, such thatthe insert extends away from a plane and resists deflection toward theplane. In many embodiments, the pre-formed shape of the insert 100 isdetermined substantially by the retention structure 110 that is coveredwith the support structure 120 comprising matrix 140 containingtherapeutic agent 130 as described herein. Alternatively, the supportstructure 120 as described herein can be configured with sufficientstiffness so as to provide the preformed three-dimensional shape providesuch that the insert can be provided without the retention structure.The insert 100 comprises a support structure 120, as described hereinsuch as a matrix 140 to contain and therapeutic agent 130. The upperportion comprises a curvature 115C1 corresponding to the upper lid ofthe patient and the lower portion 115C2 corresponding to the curvatureof the lower lid of the patient.

FIG. 2K shows a top view of an insert as in FIG. 2J extending alongnasal-temporal and anterior posterior directions and having thepreformed curved surface corresponding to the eyelids along the nasaltemporal direction to fit the eye.

FIG. 2L shows an insert 100 comprising a retention structure 110comprising hinge portions 110H and a stiff portions 110S having apreformed curved annular shape corresponding to the eyelid, such thatthe insert extends away from a plane and resists deflection toward theplane. The upper portion and lower portions comprise curvatures 115C1,115C2, respectively, corresponding to the eyelids. The hinge portions110H allow the insert to bend and fit the eye. The stiff portions allowthe upper and lower portions to extend into the upper and lower formicesof the eye. In many embodiments, the pre-formed shape of the insert 100is determined substantially by the retention structure 110 that iscovered with the support structure 120 comprising matrix 140 containingtherapeutic agent 130 as described herein. Alternatively, the supportstructure 120 as described herein can be configured with sufficientstiffness so as to provide the preformed three-dimensional shape providesuch that the insert can be provided without the retention structure.

FIG. 2M shows a top view of an insert as in FIG. 2L extending alongnasal-temporal and anterior posterior directions and having the stiffpreformed curved surface corresponding to the eyelid along the nasaltemporal direction to fit the eye.

FIG. 2N shows an isometric view of an insert 100 having a 3-D shapeprofile corresponding to a saddle shape 100S (such as a hyperbolicparaboloid) having positive curvature away from the eye along the nasaland temporal portions and opposing negative curvature toward the eyealong the inferior and superior portions, such that the nasal andtemporal portions are posterior to the inferior and superior portionswhen placed. The saddle 100S may comprise shape and curvaturecorresponding to a mathematically defined saddle such as the saddle ofastigmatism. Based on the teachings described herein, a person ofordinary skill in the art can determine the saddle shape to fit an eyeof a patient. The insert 100 may comprise the retention structure 110 asdescribed herein. This saddle shape corresponds to the shape of in situformed inserts as described herein. The superior portion of the insertcomprises a curvature 115C1 extending toward the eye of the patient, andthe curvature 115C1 is configured to correspond to the eyelid of thepatient. The inferior portion of the insert comprises a curvature 115C2extending toward the eye of the patient, and the curvature 115C2 isconfigured to correspond to the eyelid of the patient. The temporalportion of the insert comprises a curvature 115C4 extending away fromthe eye. The nasal portion of the insert comprises a curvature 115C3extending away from the eye. A contour is defined by the hyperbolicparaboloid surface and that contour may correspond to the contour of anouter edge of an embodiment of the device.

The saddle shaped insert provides upper and lower curved portionscorresponding to curvature of the upper and lower lids of the eye.

In many embodiments, the pre-formed shape of the insert 100 isdetermined substantially by the retention structure 110 that is coveredwith the support structure 120 comprising matrix 140 containingtherapeutic agent 130 as described herein. Alternatively, the supportstructure 120 as described herein can be configured with sufficientstiffness so as to provide the preformed three-dimensional shape providesuch that the insert can be provided without the retention structure.

FIG. 2O shows an isometric view of an insert having a 3-D shape profilecorresponding to a saddle having negative curvature along the nasal andtemporal portions and opposing positive curvature along the inferior andsuperior portions, such that the nasal and temporal portions areanterior to the inferior and superior portions when placed. The superiorportion comprises a curvature 115C1 away from the eye, and the inferiorportion comprises a curvature 115C2 extending away from the eye. Thenasal portion comprises a curvature 115C3 extending toward the eye, andthe temporal portion comprises a curvature 115C4 extending toward theeye. The nasal and temporal portions are located anterior to thesuperior and inferior portions so as to urge the superior and inferiorportions of the insert toward the upper and lower formices of the eye.

This insert can be similar to the insert of FIG. 2N and may comprisemany of the components and configurations of the insert of FIG. 2N,which can be rotated by 90 degrees so as to provide the placement asshown in FIG. 2O.

In many of the embodiments as described herein, and in particular withreference to the embodiments of FIGS. 2P1 to 2Z7, the pre-formed shapeof the insert 100 is determined substantially by the retention structure110 that is covered with the support structure 120 comprising matrix 140containing therapeutic agent 130 as described herein. Alternatively, thesupport structure 120 comprising matrix 140 as described herein can beconfigured with sufficient stiffness so as to provide the preformedthree-dimensional shape provide such that the insert can be providedwithout the retention structure. In either configuration, the insert mayprovide a resilient resistance to deflection, for example a hoopstrength, so as to retain the insert, and the upper, lower andintermediate portions of the insert may each have a separate resistanceto deflection so as to retain the insert.

FIG. 2P1 shows an insert 100 comprising a retention structure 110 havingan upper portion 110U comprising a first durometer 110D1 and a secondlower portion 110L comprising a second durometer 110D2. The insert canbe configured in many ways. The second durometer can be lower than thefirst durometer, for example, such that the lower portion can be moreflexible. The upper portion can slide into the upper formix, and thehoop strength of the lower portion can urge the lower portion outwardagainst the lid. By providing the lower portion with the lower durometerand lower hoop strength, the lower portion can be more easily retainedby the lower lid when the upper lid draws the retention structureupward.

FIG. 2P2 shows an insert 100 comprising a retention structure 110 havingan upper portion 110U and a lower portion 110L, in which the lowerportion is curved inward toward the eye, for example with a lower bend.The lower portion 110L may comprise bent portions 110B1, 110B2 such thatthe upper portion is urged posteriorly toward the upper formix when theinsert is placed in the eye.

FIG. 2P3 shows an insert 100 comprising a retention structure 110 havinga hinges 110H1, 110H2, to couple an upper portion 110U to a lowerportion 110L and allow the upper portion to swing toward the lowerportion. The hinges can be formed in many ways and may comprise one ormore of a break in material, a low durometer material such as a siliconematerial, a scored suture, flattened material, or combinations thereof.

FIG. 2P4 shows an insert 100 comprising a retention structure 110 havingan upper portion 110U and a lower portion 110L with bias curve such thatthe upper and lower portions extend posteriorly to the nasal andtemporal portions prior to placement. The insert comprise a curvature115C3 on the nasal side and a curvature 115C4 on the temporal side suchthat the upper and lower portions are located posterior to the nasal andtemporal portions, so as to bias the inferior and superior portionsposteriorly when the upper and lower portions are placed under theeyelids. The upper portion 110U may have a curvature 115C1 correspondingto the eyelid and the lower portion 110L may have a curvature 115C2corresponding to the lower eyelid, as described herein for example.

FIG. 2P5 shows an insert 100 comprising a retention structure 110 havingan upper portion 110U and a lower portion 110L with a biasing curve suchthat the upper and lower portions extend anterior to the nasal andtemporal portions and away from the eye prior to placement. The insertcomprise a curvature 115C3 on the nasal side and a curvature 115C4 onthe temporal side such that the upper and lower portions are locatedanterior to the nasal and temporal portions, so as to bias the nasal andtemporal portions posteriorly when the upper and lower portions areplaced under the eyelids. The upper portion 110U may have a curvature115C1 corresponding to the eyelid and the lower portion 110L may have acurvature 115C2 corresponding to the lower eyelid, as described hereinfor example.

FIG. 2P6 shows an insert 100 comprising a retention structure 110 havingan oblong shape and having first upper portion 110U and a second lowerportion 110L in which the upper portion comprises an elongate oval shapeportion so as to extend into the upper formix and the lower portioncomprises a shorter wider oval shape so as to extend into the lowerformix. The retention structure may comprise a first maximum dimensionacross 114A1 in the vertical direction and a second maximum dimensionacross 114A2 in the horizontal direction. The elongate upper portion canbe urged into the upper formix. The insert 100 may comprise combinationsof durometer. For example, the upper portion may comprise a more rigiddurometer than the lower portion. Alternatively, the lower portion maycomprise a more rigid durometer than the upper portion.

FIG. 2P7 shows an insert 100 comprising a retention structure 110comprising an upper portion and a lower portion coupled with hinges110H1, 110H2, so as to define an elliptical shape. The upper portion110U and the lower portion 110L can swing toward each other. The hinges110H1, 110H2 can be formed in one or more of many ways as describedherein. The upper portion 110U and the lower portion 110L may comprise astiff material, for example a rigid material.

FIG. 2P8 shows an insert 100 comprising a flexible redundant retentionstructure 110 to seat the retention structure in the eye. The flexibleredundant retention structure may comprise at least some hoop strengthand at least some chord length of the retention structure so as to fitthe eye.

FIG. 2P9 shows an insert comprising an upper anchor 110AN. The upperanchor may comprise an upper or lower lattice section. The upper anchormay comprise additional amounts of therapeutic agent.

FIG. 2P10 shows an insert 100 comprising a lower anchor 110AN to resistpull of the round structure. The lower anchor may comprise a cushioningshock absorbing structure sized to fit within the lower formix of theeye, for example. The lower anchor can resist pulling of the upper roundportion of the retention structure. The lower anchor may compriseadditional amounts of therapeutic agent.

FIG. 2Q shows an insert 100 comprising a retention structure 110configured to exert at least some pressure on the conjunctiva to retainthe insert. The retention structure 110 may comprise a lower surfacehaving structures to engage the conjunctiva and inhibit slipping, forexample ridges, notches, grooves.

FIG. 2R shows an insert 100 comprising a retention structure 110 havingan outer curved portion to extend laterally to the temporal formix ofthe eye. The outer temporal portion comprises an upper portion 110Uhaving a curvature 115C1 and a lower portion having a curvature 115C2,such that the outer temporal portion curves posteriorly to fit thetemporal formix.

FIG. 2S shows an insert 100 comprising a retention structure 110 havingan outer curved portion to extend laterally to the temporal formix ofthe eye. The outer curved portion comprises a solid material. The outertemporal portion comprises an upper portion 110U having a curvature115C1 and a lower portion having a curvature 115C2, such that the outertemporal portion curves posteriorly to fit the temporal formix.

FIG. 2T shows an insert 100 comprising a retention structure 110 havingan outer anchor portion 110AN to extend laterally to the temporal formixof the eye. The retention structure 110 comprises an upper portion 110Uand a lower portion 110L.

FIGS. 2U and 2V show an insert 100 comprising a retention structure 110having an upper portion 110U sized to extend into the upper formix and alower portion 110L sized to extend into a lower formix with anintermediate portion extending between the upper and lower portions. Theupper portion 110U and the lower portions 110L may each curveposteriorly from the intermediate portion so as to fit within the upperand lower formices, respectively. The upper portion 110U can be sized toextend deep into the upper formix and substantially toward the upper endof the formix so as to anchor the upper portion 110U within the eye. Thelower portion 110L can be sized to extend substantially toward the lowerend of the lower formix. The intermediate portion can be sized to extendnear the lateral canthus and medial canthus and receive the corneatherebetween with sufficient space so as to inhibit contact with thecornea. When placed on the eye 10, the upper portion 110U can extend agreater distance from the pupil than the lower portion 110L.

The portions of the retention structure can be shaped to fit the cornea.The upper portion 110U and the lower portion 110L can each be curvedposteriorly, for example bent with a biasing curve, so as to engage theupper and lower formix respectively, and urge the intermediate portionposteriorly toward the eye. For example, the upper portion can be curvedposteriorly with a third curvature 115C3 and a fourth curvature 110C4 asdescribed herein. The upper portion may comprise a curvature 115C1corresponding the eyelid as described herein. The curved upper and lowerportions may comprise the resistance to deflection to inhibit contactwith the cornea as described herein. The upper

FIG. 2W shows an insert 100 comprising a retention structure 110 havingan upper portion 110U comprising a hydrophilic surface 110HL and a lowerportion 110L comprising a hydrophobic surface 110HB. The hydrophobicsurface may comprise a sticky tacky surface to improve retention of theinsert and the hydrophilic surface may comprise a lubricous coating. Thetherapeutic agent may be provided with a support structure 120 coupledto the insert 100 as described herein.

FIGS. 2X1 and 2X2 show front and side views, respectively, of an insert100 comprising an upper portion 110U and a lower portion 110L and astiff portions 110S to angularly bias the upper portion and the lowerportion, for example toward each other. The stiff portion 110S can becoupled to the upper 110U and the lower portion 110L in one or more ofmany ways, so as to allow deflection of one or more of the upper portion110U or the lower 110L. The upper portion 110U and the lower portion110L may each comprise a resilient resistance to deflection, for examplea hoop strength as described herein. The upper end of the upper portionand the lower end of the lower portion may be inclined toward each otherat an angle, such that the upper portion and the lower portion are eachplaced in the corresponding formix of the eye and the stiff portion 110Sis placed anteriorly to the upper portion 110U and the lower portion110L.

FIG. 2Y shows an insert 100 comprising an expandable retention structure110 to allow the insert to be stretched to fit the eye. The insert maycomprise a stretchable member such as a one or more of coil, a helicalcoil, or a serpentine structure, so as to adjust the longest dimensionacross insert 100.

FIG. 2Z1 shows an insert 100 comprising a retention structure 110 havingan upper portion 110U and a lower portion 110L coupled with a variablejoint 110J to as to vary a size of the retention structure and insert.The joint 110J can be adjusted in many ways so as to vary a size of theinsert.

FIG. 2Z2 shows a telescopic joint of an insert as in FIG. 2Z1. Thetelescopic joint 110J can be configured to allow the size of the insert100 to be adjusted, for example based on a measurement of the patient.The telescopic joint can be adjusted to fit the patient, and then lockedinto position, for example by crimping the joint or applying anadhesive, for example.

FIG. 2Z3 shows a shock absorbing spring joint 110J of an insert 100 asin FIG. 2Z1. The shock absorbing joint may comprise a spring mechanismto absorb force transmitted from the lower portion 110L to the upperportion 110U, and vice versa, for example when the eye blinks or movesquickly.

FIG. 2Z4 shows a ratcheting joint 110J of an insert as in FIG. 2Z1. Theratcheting joint 110J may comprise a sliding mechanism to receive theupper portion 110U of the insert and the upper portion can be advancedin to the ratcheting joint 110J so as to decrease a size of the insert,for example based on a measurement of the eye as described herein. Theratcheting mechanism may comprise one or more known ratchetingmechanisms and may comprise at least one tooth and a plurality ofgrooves so as to adjust the circumferential length of the insert.

FIGS. 2Z5 and 2Z6 show front and side views, respectively, of an insert100 comprising an elongate shape having upper and lower portions sizedto extend into upper and lower formices, respectively, so as to providesubstantially greater amounts of therapeutic agent 130 than theintermediate portions locatable near the lateral and medial canthus. Theinsert 100 may comprise a retention structure 110 comprising an upperportion 110U and a lower portion 110U. The upper portion 110U can extendinto the upper portion of the insert so as to support and providestiffness to the upper portion of the insert. The lower portion 110L canextend along the lower portion of the insert so as to provide supportand stiffness to the lower portion of the insert. The upper portion ofthe insert and the lower portion of the insert may comprise a thicknessgreater than the intermediate portion of the insert, so as to containsubstantial amounts of therapeutic agent with the each of the upper andlower portions of the insert.

FIGS. 2Z7 and 2Z8 show front and side views, respectively, of a rigidinsert 100 having a curved shape sized to fit the eye of the patientsuch that the insert can be worn comfortably for an extended time. Therigid insert 100 may comprise one or more materials as described herein,for example polyacrylate, polycarbonate, metal, or other material. Therigid insert may comprise a rigid matrix 140 comprising a therapeuticagent 130. The rigid insert can be sized such that contact of the innerportion with the cornea is inhibited, and such that the outer portionextends to the formix of the eye when placed. The insert can be adheredto a portion of the eye, for example with an adhesive or other materialor structure as described herein.

The embodiments of 2A to 2Z7 are provided as non-limiting examples andcan be combined and modified in many ways. In many embodiments, theinsert is provided with a drug delivery matrix material having a one ormore of a stiffness or spring bias corresponding to the above describedretention structures, such that the insert can be provided without askeletal structure and provide the function of the skeletal structure.For example, the drug delivery matrix may comprise materials having adurometer and cross-sectional dimensions so as to provide the functionof the retention structure. Alternatively or in combination, a supportstructure as described herein such as the drug delivery matrix can beprovided over the retention structure as described herein, for example.

FIG. 3A1 shows an insert placed between folds of conjunctiva. The insertcan be placed between the bulbar conjunctiva and lid of the eye suchthat the insert is placed between one or more folds 56F of the bulbarconjunctiva and one or more folds 58F of the palpebral conjunctiva, forexample. The insert 100 comprising the resistance to deflection caninteract with the conjunctiva in many ways and can one or more ofstretch the conjunctiva, form a fold of conjunctiva, deform theconjunctiva, deform the conjunctiva to form a fold, deform theconjunctiva to form a flap of conjunctiva, embed within folds ofconjunctiva, or fit between the folds of conjunctiva, as describedherein, so as be retained comfortably on the eye for an extended time.The insert 100 comprising the resistance to deflection can stretch orcompress, the conjunctiva in many ways and so as to receive the insert.For example, the insert can be placed between the bulbar and palpebralconjunctiva so as to one or more of stretch or compress the bulbarconjunctiva 56 and the palpebral conjunctiva 58 so as to comfortablyretain the insert therebetween. The one or more of stretching orcompression of the bulbar conjunctiva can form a fold of conjunctiva, orreshape the conjunctiva so as to retain the insert 100.

FIG. 3A2 shows a fold of conjunctiva receiving the insert 100. Theinsert 100 may be received with a naturally occurring fold ofconjunctiva, or a fold created with the insert 100. The insert 100 maydisplace the conjunctiva so as to shape the conjunctiva. For example,the conjunctiva can be molded with the insert 100. The insert 100comprising the resistance to deflection as described herein can urge anddisplace the conjunctiva to receive the insert. For example, the insert100 comprising the resistance to deflection can urge of conjunctiva suchthat the conjunctiva can be deformed and insert received with thedeformed conjunctiva, for example in a fold of deformed conjunctiva. Inmany embodiments, the folds of conjunctiva can be urged with the inserthaving the resistance to deflection such that a fold is formed in theconjunctiva and shaped to receive the insert. The insert 100 having theresistance to deflection may form a pocket within the conjunctiva toreceive the insert within the pocket, for example. The insert 100 can beconfigured with the resistance to deflection in many ways to shapeand/or deform the conjunctiva as described herein, for example withretention structure 110 or alternatively without retention structure110.

FIG. 3A3 shows an insert sized to fit between folds of conjunctiva. Theinsert may comprise a size corresponding to the one or more folds ofconjunctiva, such that the insert can fit one or more folds ofconjunctiva. The insert 100 may comprise sufficient resistance todeflection so as to shape the conjunctiva and to receive the insert, forexample with a fold or pocket.

FIG. 3A4 shows a retention structure of an insert as in FIGS. 2A to 2Cplaced on an eye such that the retention structure fits into one or moreof a plurality of folds 56F of the bulbar conjunctiva 56 located awayfrom formix 54. The retention structure 110 can be received in one ormore of the several folds 56F of conjunctiva located between the formix54 and cornea 12. In many embodiments, each of the plurality of folds ofthe bulbar conjunctiva comprises an invagination corresponding to aninvagination depth, and the cross-sectional dimension of the retentionstructure corresponds to the invagination depth such that the elongateretention structure fits within and extends along the invagination. Theretention structure 110 can be received in one or more of the folds 58Fof palpebral conjunctiva 58F located between the formix 54 and lidmargin, for example when the retention structure 110 moves with the eye.The retention structure 110 may comprise the resistance to deflection soas to urge the retention structure 110 to fit within the fold, forexample.

FIG. 3B shows a retention structure under a fold 56F of bulbarconjunctiva. The fold 56F of bulbar conjunctiva can extendcircumferentially around the eye about axis 10A of the eye. Theretention structure 110 can be deflectable along the fold 56F such thatthe retention structure 110 can be retained in the fold. Alternativelyor in combination, the retention structure 110 may comprise sufficientresistance to deflection so as to deform the conjunctiva such that thefold of conjunctiva extends over the retention structure. The retentionstructure 110 may comprise the resistance to deflection as describedherein such that the movement of retention structure 110 toward thecornea can be inhibited substantially when the retention structure 110is received within the fold 56F. The retention structure 110 can besimilarly received and deflect along folds 58F of the palpebralconjunctiva away from formix 54. Alternatively, the matrix materialinsert 100 may comprise the resistance to deflection without retentionstructure 110, such that the insert 100 can fit under the folds ofbulbar conjunctiva.

FIGS. 3C1 to 3C3 show a retention structure 110 under a fold 56F ofbulbar conjunctiva 56 moving with rotation of the eye 10. The retentionstructure can be retained within the sac away from formix 54 at aninitial location of the fold 56F as shown in FIG. 3C1. The eyeball canrotate such that the fold 56F moves with the eyeball toward a margin 40Mof the lid 40 as shown in FIG. 3C2. The lid margin 40M can be moved awayfrom the fold 56F such that the retention structure 110 can be seenunder the flap 56F of conjunctiva.

FIG. 3D shows an initial inferior placement of support structure 120 ofinsert 100 in an eye such as a left eye of a patient. The retentionstructure 110 and support structure 120 are configured to allow rotationof the insert 100 around the axis 10A of the eye, for example inresponse to cyclo torsional movement of eye 10 about axis 10A. Theretention structure 110 comprises the resistance to deflection asdescribed herein, and the support structure 120 comprises the firstinclined surface of first tapered end portion 122 and the secondinclined surface of second tapered end portion 124 to allow sliding ofthe support structure 120 and retention structure 110 along theconjunctival sacs.

FIG. 3E shows insert 100 initially placed as in FIG. 3D which has movedrotationally along the conjunctiva about an axis of rotation extendingthrough pupil 16 of the eye 10. The insert is shown in an inferiortemporal location of the sac, and this self-seating migration of theinsert can provide improved comfort for the patient. The resistance todeflection of the retention structure 110 can be configured so as toallow the retention structure 110 to bend within the sac and permitmovement such as rotation of the retention structure and supportstructure 120. The inclined surfaces of the support structure 120 canallow movement of the support structure along one or more locations ofthe conjunctiva. For example, the inclined surfaces may urge the inserttoward the inferior temporal location in response to one or more ofmovement of the eye, cyclo torsional movement of the eye, or increasedclearance for the insert away from the skull within the sac. Work inrelation to embodiments described herein suggests that cyclo torsion ofthe eye can be related to rotational movement of the insert 100. In atleast some patients, the orbit of the eye has an elongate horizontal(i.e. nasal-temporal) dimension near the rim so as to provide increasedclearance for the insert compared with the inferior location shown inFIG. 3D.

FIG. 3F shows an insert located at an inferior temporal location of thelower conjunctival sac of the eye and the orbit, such as an orbit of aright eye of the patient. The bony orbit BO of the skull of the patientis defined at least in part by a bony rim BR extending around the eyesocket. The bony orbit comprises a first nasal temporal maximumdimension across substantially aligned with the palpebral fissure PF anda second superior inferior maximum dimension across transverse to thepalpebral fissure PF. The outer dimension of the sclera 24 of fitswithin the bony orbit BO. In many embodiments, the retention structure110 of insert 100 is sized in proportion to the maximum diameter of thesclera transverse to the optical axis of the eye, for example to withinabout two millimeters of the maximum diameter of the sclera transverseto the optical axis of the eye. In many embodiments, the retentionstructure 110 deflects when placed in the eye as described herein.

The bony orbit comprises dimensions to receive the insert in theconjunctival sac and allow movement of the insert within theconjunctival sac and retain the insert. The maximum dimension across theadult human eye transverse to the axial length is about 24 mm, and thedimension of palpebral fissure is about 30 mm. The first nasal temporalmaximum dimension across the bony orbit is greater than the secondsuperior inferior dimension across. In the adult human, dimensions ofbony orbit are about 40 mm long and about 30 mm vertically. The anteriorentrance of the orbit can form a rough rectangle measuring approximately43 mm (within a range from about 36-47 mm) wide by 34 mm (within a rangefrom about 26-42 mm) high, as described in the Atlas of Clinical andSurgical Orbital Anatomy, published on the world wide web(expertconsultant.com). The orbit may attain a widest dimension at about15 mm behind the bony rim, such that the rim may constrain rotationalmovement of the retention structure 110 and support structure 120 ofinsert 100, for example with cyclo torsion of the eye.

In some patients, the superior-inferior dimension across the bony rim BRof the bony orbit BO increases temporally away from the middle of thebony orbit, so as to define an inferior temporal location of the bonyorbit corresponding to a location of the inferior conjunctival sachaving an increased size to accommodate the support structure 120 ofinsert 100. The support structure 120 can be sized to fit comfortablywithin the inferior temporal location and allow rotation of insert 100with cyclotorsion or other movement of the eye 10, for example. Work inrelation to embodiments suggest that the first inclined surface of firsttapered end portion 122 and the second inclined surface of secondtapered end portion 124 can be subjected to different pressures of theconjunctiva within the sac such that the support structure 120 may beurged toward the inferior temporal location of the lower conjunctivalsac.

FIG. 3G shows the support structure 120 and retention structure 110 asdescribed herein placed superiorly. The superior placement can be usedwith patients who may have a droopy lower eyelid, for example. The upperlid can retain the support structure 120 comprising the therapeuticagent 130 contained within matrix 140, for example. The retentionstructure 110 can be sized to fit within one or more of the plurality offolds of the inferior conjunctiva, for example the inferior bulbarconjunctiva as described herein.

FIG. 3G-1 shows the support structure placed superiorly at an initiallocation of the superior conjunctival sac 52. The superior conjunctivalsac 52 comprising upper lid 42 can receive the support structure 120comprising therapeutic agent 130 contained within matrix 140, and thepressure of the upper lid can urge the support structure upward towardthe cul-de-sac and formix.

FIG. 3G-2 shows the support structure 120 seated in the cul-de-sac 53comprising formix 54 of the superior conjunctival sac 52 followingplacement as in FIG. 3G-1. The retention structure 110 can extend alongthe lower sac and fit within the one or more folds of the lower sac, forexample bulbar folds, as described herein.

FIG. 3H shows the support structure 120 located at an inferior nasallocation of the eye so as to extend near the caruncle. The supportstructure 120 may comprise a low resistance to deflection, for exampleless than the retention structure 110, such that the support structureand retention structure can deflect together on the eye. This lowresistance to deflection can permit placement of the support structure120 at many locations as described herein.

FIG. 3I shows the support structure 120 placed at a temporal location ofthe eye.

FIG. 3J shows retention structure 110 comprising a first portion 162having a first resistance to deflection and a second portion 164 havinga second resistance to deflection less than the first portion. The firstresistance to deflection less than the second resistance to deflectionmay comprise one or more of a varying thickness of retention structure110, a varying material of retention structure 110 or a plurality ofmaterials of retention structure 110. The first portion 162 may comprisea greater cross sectional dimension; e.g., diameter, than the secondportion, so as to increase the resistance to deflection of the firstportion relative to the second portion, for example. This increasedresistance to deflection can permit the first portion 162 of theretention structure to be placed under the superior (upper) lid so as toinhibit movement of the first portion 162 toward the cornea. The sizingof the first portion 162 can urge the first portion toward the formix54. The relatively smaller cross-sectional size of the second portion164 can permit the second portion to fit within the one or more folds ofthe inferior (lower) sac of the eye as described herein.

FIG. 3J-1 shows a side cross sectional view of the retention structure110 as in FIG. 3J. The retention structure 110 may comprise a crosssectional dimension 112 of the elongate second portion of the retentionstructure, and a cross sectional dimension 113 of the first portion 162of the retention structure. The first portion 162 and the second portion164 may comprise substantially the same material such that the thinnersecond portion has the resistance to deflection lower than the thickersecond portion as described herein.

FIG. 3K shows an insert 100 comprising a support structure 120comprising a matrix 140 of therapeutic agent 130 on the retentionstructure 110 as in FIG. 3J. The support structure 120 can be located onretention structure 110 so as to correspond to one or more supportstructure locations as described herein, such as nasal placement,temporal placement, inferior placement, superior placement, or inferiortemporal placement, when the wider first portion 162 is placedsuperiorly, for example. For example, the support structure 120comprising the matrix 140 and the wider first portion 162 can be placedsuperiorly, for example. Alternatively or in combination, the supportstructure 120 comprising matrix 140 of therapeutic agent 130 can beplaced at one or more of many locations on the retention structure 110corresponding to one or more locations of the eye when the first portionis placed superiorly. For example, the support structure 120 comprisingmatrix 140 containing therapeutic agent 130 can be located on retentionstructure 110 for placement inferiorly when the wider first portion 162is placed superiorly, for example.

FIG. 3L shows an insert comprising a lubricous coating. The lubricous170 coating can allow the insert to move along the conjunctiva of theeye and can cover one or more of the retention structure 110 or thesupport structure 120. For example, the lubricous coating may cover thesupport structure 120 comprising matrix 140 containing therapeutic agent130, and the therapeutic agent 130 can be released through the surfaceof the matrix 140 as described herein. Alternatively or in combination,the lubricous coating may cover at least a portion of the retentionstructure. For example the lubricous coating 170 may cover a portion ofthe retention structure corresponding to locations near the lacrimalgland. Alternatively, the lubricous coating 170 may cover the supportstructure and the retention structure, for example with dip coating ofinsert 100.

FIG. 3L-1 shows a layer 172 of the lubricous coating 170 on a surface172 of the matrix 140 as in FIG. 3L. The layer 172 may extend over thesurface the matrix 140 that releases the therapeutic agent as describedherein. The therapeutic agent 130 can be released through the layer 172,and the rate of release can be determined substantially by surface areaof the matrix 140 and the solubility of the therapeutic agent in thetear of the eye.

The lubricous coating may comprise one or more of an oil, a surfactant,a hydrogel, polyvinyl alcohol (PVA), hydroxyethyl methacrylate (HEMA),sodium polyacrylate, acrylate polymers and copolymers having hydrophilicgroups, N-vinylpyrrolidone (NVP), agarose, methylcellulose, ethyleneoxide (ETO), polyethylene oxide (PTO) or hyaluronan, for example.

FIG. 4A shows an insert comprising a plurality of therapeutic agentsloaded on a first portion of the support structure 120 and a secondportion of the support structure 120. The support structure 120 can beconfigured to reside in the inferior temporal location of theconjunctival sac or other location as described herein. The plurality oftherapeutic agents may comprise therapeutic agent 130 contained withinmatrix 140 and a second therapeutic agent 132 contained within a secondmatrix 142, for example. The first matrix 140 and second matrix 142 maycomprise similar materials, for example silicone elastomer comprisingsiloxane. While many matrix materials can be used, work in relation toembodiments suggests that known commercially available siliconeelastomer from NuSil can be used as the matrix material.

FIG. 4B shows a matrix comprising inclusions 131 of a therapeutic agent130 in matrix 140. The inclusions 131 may comprise particles of thetherapeutic agent such as one or more of solid particles, liquidparticles, crystals or droplets of the therapeutic agent within thematrix 140. The solid particles can provide release of therapeuticamounts of the therapeutic agent for an extended time, and the releaserate connects can be one of more of zero order release, first orderrelease, or intermediate release rates, or combinations thereof. Forexample, the release rate can be substantially zero order when theinclusions 131 remain in the matrix and transition to substantiallyfirst order when the inclusions have substantially dissolved.

FIG. 4C shows support structure 120 comprising a plurality of supportstructures, in which the plurality of support structures comprise aplurality of therapeutic agents placed together on a retention structureat a location corresponding to placement along an inferior temporalportion of the conjunctiva of the eye. The plurality of supportstructures can be spaced apart so as to extend a distance 126 onretention structure 120 suitable for placement along the inferiortemporal portion of the conjunctival sac as described herein. Theplurality of structures may comprise therapeutic agent 130 within matrix140 to release the therapeutic agent and second therapeutic agent 132within second matrix 142 to release the second therapeutic agent.

FIG. 4D shows a support structure 120 comprising a plurality of supportstructures located along retention structure 110 to release thetherapeutic agent 130. The plurality of support structures can be shapedin many ways, and may comprise round objects such as spherical balls, orcylinders, for example. The plurality of support structures can extend adistance along retention structure 110 for placement in the inferiortemporal location of the conjunctival sac. The plurality of objects mayincrease the surface area of the matrix to increase the rate of releaseof the therapeutic agent with the increased surface area, for example.

FIG. 4E shows release of a therapeutic agent from a matrix 140 having asurface area sized to treat the patient for an extended time. The matrix140 comprises a surface area defined substantially by distance 126 andcross sectional dimension 127, such as a diameter. The cross-sectionaldimension may correspond to a distance around the structure 120 such asa circumference 127C. The area of the matrix 140 may correspondsubstantially to the circumference 127C multiplied by the distance 126.

FIG. 4F shows release of a therapeutic agent from a spherical surface ofa support structure 120 comprising matrix located on a retentionstructure 110. The spherical surface has an area to release therapeuticamounts of the therapeutic agent for the extended time. The structure120 comprises dimension across 127, which may comprise a diameter acrossthe spherical structure. The surface area of the matrix can be readilydetermined in many ways by one of ordinary skill in the art, for exampleby the relationship: Surface Area=PI*(Diameter)^2.

FIG. 4G shows support structure 120 comprising a plurality of at leastthree support structures along a retention structure comprising aplurality of at least three therapeutic agents. The structure comprisingthe at least three therapeutic agents can extend a distance 126 forplacement in the conjunctival sac, for example within an inferiortemporal portion of the sac as described herein. The at least threesupport structures may comprise a first support structure 120Acomprising a first therapeutic agent 130, a second support structure120B comprising a second therapeutic agent 132 and a third supportstructure comprising a third therapeutic agent 134. The firsttherapeutic agent 130 can be contained within first matrix 140, thesecond therapeutic agent 132 contained within second matrix 142 and thethird therapeutic agent 134 contained within third matrix 144. Each ofthe therapeutic agents may be contained on one or more matrices of oneor more support structures.

FIG. 4G-1 shows a plurality of support structures comprising a firsttherapeutic agent contained within a first matrix and a secondtherapeutic agent contained within a second matrix. The insert 100 maycomprise a support structure 120 comprising a plurality of segments inwhich each segment comprises a matrix to contain a therapeutic agent.The first segment 120ASA may comprise the first therapeutic agent 130contained in the first matrix 140 as described herein. The secondsegment 120BSA may comprise the second therapeutic agent 132 containedin a second matrix 142. The first segment can be separated from thesecond segment with a separator 120S. The first segment, the secondsegment, and the separator may comprise similar materials, for examplesilicone elastomer, such that the first segment and the second segmentcan bond to the separator. Each of the segments may comprise segments ofa ring and be sized to slide along the conjunctival sacs with torsion asdescribed herein. The retention structure 110 may extend through each ofthe segments and the separator.

The surface area and loading of the therapeutic agent of each segmentmay correspond to the rate of release of each therapeutic agent. Forexample, different regions of the insert, for example different segmentsmay have different drugs and surface areas of the matrix for differentrelease rates. The first therapeutic agent may comprise a prostaglandinsuch as one or more of bimatoprost, latanoprost, or travoprost, and thesecond therapeutic agent may comprise a beta blocker such as timolol.The beta blocker can be released at a rate that is faster than theprostaglandin, for example within a range from about 5 to 20 times therate of release of the prostaglandin, for example 10×. The portion ofsupport structure 120 comprising the beta blocker may comprise aproportionally greater surface area to provide the rate of release, forexample a surface area that is at least about twice the surface area ofthe prostaglandin, for example a surface area within a range from about5 to 20 times the surface area of the prostaglandin. The prostaglandinand the beta blocker may each comprise inclusions within the first orsecond matrix, respectively.

Each segment comprising the surface area and therapeutic agent may becoated. The coating may comprise a material that readily passes thetherapeutic agent, such as a hydrogel. Alternatively, the coating maycomprise a material that inhibits release of the therapeutic agent, anda size and number of the holes for each segment configured to releasethe therapeutic agent at therapeutic rates for an extended time. Forexample, the size and number of holes of the segment comprising the betablocker can provide at least about 2 twice the surface area to releasethe beta blocker, for example at least about 5 to 20 times the surfacearea to release the beta blocker relative to the prostaglandin. In manyembodiments, one or more of the support structure 120 and the retentionstructure 110 comprise a pre-insertion three dimensional shape profileas described herein, for example to resist deflection away from theinferior bulbar conjunctiva.

FIG. 4G-2 shows a retention structure comprising a ring, in which thering comprises a plurality of ring segments. The retention structure 110may comprise the support structure 120 to contain the therapeutic agent130. The ring segments may comprise different drugs at different rateson single ring. The insert 100 comprising the ring structure maycomprise a substantially constant cross-sectional diameter, or a varyingcross-sectional diameter as described herein. The insert 100 comprises afirst support portion 120A comprising a first therapeutic agent 130, asecond support portion 120B comprising a second therapeutic agent 132and a third portion substantially without therapeutic agent andcomprising a retention structure 110. The first portion 120A can beseparated from the third portion with a first separator 120S1. The firstportion 120A can be separated from the second portion 120B with a secondseparator 120S2. The second portion can be separated from the thirdportion with a third separator 120S3. Each of the first portion 120A,the second portion 120B, the third portion, the first separator, thesecond separator and the third separator may comprise a similarmaterial, for example silicone. The portions can contact the separatorsso as to bond to the separators when the portions are cured, such thatthe insert may comprise a plurality of segment portions bonded togetherwith the separators.

FIG. 4G-3 shows an annular insert comprising a retention structurecomprising 100 an annular ring and an annular support 120 comprising amatrix 140 of therapeutic agent 130 covering the retention structure.The annular support structure 120 comprises a cross-sectional dimension127 sized to provide therapeutic amounts of the therapeutic agent forthe extended time. The matrix may comprise one or more of many materialsas described herein, for example silicon and therapeutic agent.

FIG. 4G-4 shows a cross-sectional view of the retention structure andsupport structure of FIG. 4G-3. The cross-sectional dimension 117Dacross the retention structure 110 is sized to provide the resistance todeflection so as to retain the insert within the eye, for example withthe hoop strength. The retention structure 110 may comprise one or moreof many materials as described herein, such as a silicone having adurometer of at least about 60 A, for example a durometer of 80 A. Inmany embodiments, the retention structure 110 comprises a durometer lessthan the durometer of matrix 140.

An insert comprising unitary structure can be utilized with the drugeluting structure and resistance to deflection, as described herein. Theunitary insert can be configured so as to provide deflection, and drugrelease as described herein. The insert may comprise inclusions of atherapeutic agent contained in a matrix as described herein. The matrixcontaining the therapeutic agent may comprise strength and resistance todeflection similar to the insert comprising the skeleton as describedherein. The matrix 140 may comprise a support 120 comprising a supportmaterial of the matrix. The matrix 140 may comprise a support materialhaving a hardness so as to provide the resistance to deflection asdescribed herein, such that the function of the retention structure canbe provided by the matrix 140 without the retention structure, forexample. The support material may comprise one or more of a silicone, apoly acrylate, or a polycarbonate for example, having a harnesssufficient to provide the resistance to deflection.

The cross-sectional dimension across a portion of the insert can besized to provide the resistance to deflection so as to retain the insertwithin the eye, for example with the resistance to self-loadingdeflection as described herein. The material may comprise a durometer of50 A or more, for example 80 A or more, so as to provide the resistanceto deflection. In many embodiments, the unitary insert comprises asilicone material having a durometer of about 80 A or more, andinclusions of the therapeutic agent.

The unitary insert comprising one or more of the resistance todeflection, the resistance to self-loading deflection, the self-loadingdeflection angle, the torsional resistance twisting, or the hoopstrength, or combinations thereof as described herein, can be combinedwith any one or more shapes or structures as described herein. Forexample, the unitary insert may comprise the one or more of self-loadingresistance to deflection, the self-loading deflection angle, the hinges,the 3D shape profile, the bias, the curved bias, or the dual durometerupper and lower portions, for example, with reference to Tables 1A to 1Dand FIGS. 2A to 2Z7, for example.

FIG. 4H shows an insert 100 comprising a support structure 120comprising an at least partially erodible structure 170 comprising anerodible material 176 to release a therapeutic agent 130 for an extendedtime. The erodible structure 170 can be coupled to the retentionstructure 110 as described herein.

FIG. 4I shows a transverse cross sectional view of the at leastpartially erodible structure 170 comprising the erodible material 176 asin FIG. 4H. A barrier material 174 is shaped to define a chamber 172 ofthe support structure 120. A channel 173 extends from chamber 172 to anopening to release the therapeutic agent. The channel 176 can be blockedwith an erodible material to inhibit release of the therapeutic agent130 contained in the chamber. When material 176 erodes, the channel 173opens to release the therapeutic agent.

FIG. 4J shows a side cross sectional view of the structure 170comprising the erodible material 176 as in FIGS. 4H and 4I. A pluralityof chambers may contain therapeutic agent 130, and the plurality ofchambers may comprise a first chamber 172 and a second chamber 174. Theerodible material may be located on a substantially non-erodiblesupport, such as a substrate 178, and the erodible material occupy achannel defined with a substantially non-erodible material, such thatthe material erodes along an exposed surface of the material. Thesubstrate 178 can be positioned on a first side of the erodible materialand the plurality of chambers on a second side of the erodible materialso as to define an erosion path 179. The erosion path may comprise alinear path, and the containers may comprise openings arranged along thelinear path to release the therapeutic agent from each container insequence. The erosion path can be linear, for example straight, orcurved. The erosion path can be arranged to sequentially release thetherapeutic agent from each of the plurality of chambers, for examplefrom the first chamber first and the second chamber second.Alternatively, the order can be reversed. The rate of erosion andspacing of the chambers can be arranged so as to release an amount ofthe therapeutic agent at substantially regular intervals, for exampledaily. The plurality of chambers and erodible material can be arrangedin many ways to release the therapeutic agent at regular intervals foran extended time of at least one week, for example one month or moresuch as an extended time of two or more months. For example, theplurality of chambers may comprise 90 chambers to release a therapeuticamount each day for at least about three months. The plurality ofchambers may comprise 180 or more chambers to provide the extendedrelease for at least about 6 months, for example. The sizing of thechambers and spacing can be manufactured in many ways, for example withnano-technology and etching to form the chambers and deposition to formthe erodible material.

FIG. 4K shows a reservoir chamber having channel 173 occluded witherodible material 176 as in FIGS. 4H to 4J.

FIG. 4L shows the container as in FIG. 4K having the material 176 erodedaway from the channel to release the therapeutic agent 130 from thereservoir chamber.

FIG. 4M shows a pump 180 to release a therapeutic agent 130 withpulsatile flow. The pump 180 may comprise one or more of many pumps suchas an osmotic pump 182, and active pump such as amicro-electro-mechanical (hereinafter “MEMS”) pump. The pump can beconfigured to provide pulsatile flow at regular intervals so as torelease the therapeutic agent 130 at regular intervals.

The pump 180 may comprise an osmotic pump 182 coupled to a valve 186configured to open at regular intervals. The pump 180 can be coupled toa chamber 183 enclosed with an elastically expandable barrier materialsuch as an elastic membrane 184 so as to contain therapeutic agent 130.The chamber 183 can swell in volume in response to increased pressure soas to elastically stretch the membrane 184. The valve 186 can open inresponse to increased pressure of the chamber 183 so as to release apulsatile amount of therapeutic agent 130 from the chamber 183 into theeye.

FIG. 4N shows a release profile of therapeutic agent 130 of the pump 180as in FIG. 4M. The release profile corresponds to an amount oftherapeutic agent released over a time. The pulsatile release profilemay comprise a bolus of therapeutic agent released at substantiallyregular intervals, for example approximately twice per day. The bolus oftherapeutic agent 130 can be released at the substantially regularintervals for at least about one month, for example at least about twoor more months. In many embodiments, the therapeutic amounts of thetherapeutic agent can be released with pulsatile flow at substantiallyregular intervals for at least about 3 months (90 days), for example 4months, or 6 months or more.

FIG. 4O shows a pressure profile of a chamber of the pump as in FIGS. 4Mand 4N. When the pressure in the chamber reaches a threshold amount, thevalve 186 can open substantially so as to release a therapeutic amountof the therapeutic agent 130 with pulsatile flow as shown with one ofthe peaks of the profile of FIG. 4N.

FIG. 4P shows a container 190 comprising inclusions 131 of a therapeuticagent coupled to an osmotic pump 180 with a movable or deflectablecomponent 196 such as one or more of a piston or a diaphragm, so as torelease therapeutic agent with pulsatile flow. The container maycomprise a material 198 to inhibit release of the therapeutic agent. Thematerial 198 may extend substantially around the container 190 so as todefine a chamber 192. The chamber 192 may have a reservoir oftherapeutic agent contained therein. The pump 180 may comprise theosmotic pump 182 coupled to a valve 186 such that the valve 186 can opento advance the movable or deflectable component 196 with pressure. Themovable or deflectable component 196 may comprise a piston that can beadvanced toward chamber 192 with deflection so as to decrease a volumeof the chamber and release therapeutic agent 130 from the chamber 192with pulsatile flow, for example. The movable or deflectable component196 may comprise a diaphragm that can be advanced toward chamber 192with deflection so as to decrease a volume of the chamber and releasetherapeutic agent 130 from the chamber 192 with pulsatile flow, forexample.

The container 190 can be configured in many ways to release thetherapeutic amounts of the therapeutic agent 130 with pulsatile flow.The container 190 may contain inclusions 131 of therapeutic agent 130that is nearly insoluble in water, for example a prostaglandin such aslatanoprost or bimatoprost. The pulsatile flow of the pump can increasethe pressure to the container 190 with coupling of the movable ordeflectable component 196. The pressure pulse can decrease the volume ofthe chamber such that the therapeutic agent is released from thecontainer with pulsatile flow. The chamber 192 can be substantiallydefined with a material 198 such that the volume of the chamber 192decreases when the movable or deflectable component 196 such as a pistonadvances toward chamber 192. In many embodiments, at least a portion ofthe chamber comprises a porous structure having pores sized to releasemolecules of the therapeutic agent and substantially inhibit release ofthe inclusions of the therapeutic agent, such that molecules of thetherapeutic agent can be released with the pulse and release of theinclusions substantially inhibited.

FIG. 4Q shows reservoir chamber comprising inclusions of a therapeuticagent coupled to valve of an osmotic pump so as to release therapeuticagent with pulsatile flow.

An insert can comprise a retention structure and a support structurecomprising a reservoir chamber to contain a therapeutic agent and apassive diffusion release mechanism to release the therapeutic agent 13.The retention structure may comprise one or more of the retentionstructure components as described herein, for example a wire. Thesupport structure may comprise one or more support structures asdescribed herein, for example a container comprising a chamber tocontain therapeutic agent. The support structure may comprise one ormore mechanisms to release the therapeutic agent with controlleddiffusion, for example one or more holes in the container extending tothe chamber. The support structure may comprise metal, for example, andthe retention structure may comprise metal that can be fastened to themetallic support structure in one or more of many ways, for example withwelding. The retention structure may comprise the resistance todeflection as described herein to retain the insert within the eye, forexample.

An insert can comprise a retention structure and a support structurecomprising a reservoir chamber to contain a therapeutic agent and amechanism to release the therapeutic agent in response to blinking ofthe eye. The reservoir chamber may comprise a wall that can be one ormore of folded, rolled or compressed, such that pressure exerted whenthe eye blinks can be transmitted to the reservoir chamber so as torelease the therapeutic agent. The mechanism to release the therapeuticagent 130 may comprise one or more mechanisms capable of releasing thetherapeutic agent in response to pressure, such as a plurality ofopenings, a valve, or a membrane, for example. The mechanism can becoupled to the wall of the reservoir chamber so as to releasetherapeutic agent in response to blinking of the eye.

The insert configured to release therapeutic agent in response toblinking can have the benefit of providing additional therapeutic agentas needed. For a patient having dry eye, the patient is more likely toblink when the eye has less hydration and less likely to blink when theeye has more liquid. By providing a therapeutic agent released inresponse to blinking, the patient can receive a greater amount oftherapeutic agent when the eye is dry and more therapeutic agent isappropriate, and the eye can receive less therapeutic agent when the eyeis hydrated and additional therapeutic agent of lesser benefit. Thetherapeutic agent may comprise one or more of many therapeutic agentssuitable for treating the eye as described herein, and in manyembodiments suitable for treating dry eye such as one or more of alipid, a phospholipid, an oil, or a silicone oil, for example.

The insert configured to release therapeutic agent in response toblinking can be configured to release therapeutic agent in response tothe patient pressing on the insert, for example, such that the patientcan administer additional therapeutic agent as appropriate.

FIG. 5A shows an insert comprising a lentoid retention structure 110having an end portion 116 shaped to inhibit contact with the caruncle ofthe eye when placed on the eye when the support structure 120 comprisingthe therapeutic agent 130 is placed on the inferior temporal location ofthe eye. The end portion 116 can be shaped in many ways to inhibitcontact with the caruncle and may comprise an indent, for example. Thesupport structure 120 may comprise a crescent profile comprising firstinclined surface of first tapered end portion 122 and second inclinedsurface of second tapered end portion 124 as described herein. Thelentoid structure may comprise an upper curved portion for placementunder the upper lid and a lower curved portion curved for placementunder the lower lid, and the radius of curvature of each of the uppercurved surface and the lower curved surface can be dimensioned tocorrespond with dimensions of the upper formix and lower formix,respectively.

FIG. 5B shows an insert 100 comprising a lentoid retention structure 110having end portion 116 and decreased width to inhibit contact with thecaruncle of the eye when placed on the eye when the support structure120 comprising the therapeutic agent 130 is placed on the inferiortemporal location of the eye.

FIG. 5C shows insert 100 comprising a retention structure 110 shapedwith an inward extension 117 to inhibit irritation of the lacrimal glandand an inward extension 116 to inhibit contact with the caruncle of theeye. The extension 117 can extend a distance so as to inhibit contactand engagement of the conjunctival tissue over the lacrimal gland, andthe distance may correspond to about 90 degrees around the pupil of theeye, for example. The extension 117 can deflect inward, or outward, fromthe retention structure, for example. The extension 116 can extend adistance so as to inhibit contact and engagement of the retentionstructure 110 with the caruncle, and the distance may correspond toabout 90 degrees around the pupil of the eye, for example. The extension116 can deflect inward, or outward, from the retention structure, forexample.

FIG. 5D shows an insert 100 comprising a retention structure 110 shapedwith an outward extension 117 to inhibit irritation of the lacrimalgland of the eye.

FIG. 5E shows an insert 100 comprising a retention structure 110 shapedwith an inward extension 117 to inhibit irritation of the lacrimal glandof the eye.

FIG. 5F shows an insert 100 comprising a retention structure 110 havingan open end portion 118 to inhibit irritation of the lacrimal gland ofthe eye. The open end portion 118 comprises a first end 119 and a secondend 119 having a gap extending there between to inhibit contact of thetissue near the lacrimal gland. The gap may correspond to about ninetydegrees of arc around the globe so as to inhibit contact with the tissuenear the lacrimal gland. The first end 119 and the second end 119 maycomprise an increase cross sectional size in relation to the elongateportion of the retention structure to inhibit penetration of theepithelium, for example.

FIG. 5G shows an insert 100 comprising a retention structure having asoft material 117S to inhibit irritation of the lacrimal gland and thecaruncle of the eye. The soft material 117S may comprise a hydrogel orother soft material, for example. The soft material 117S may extend overan elongate portion of the retention structure 110, or the retentionstructure 110 may comprise a first end and a second end as describedherein having the soft material extending between the first end and thesecond end.

FIG. 5H shows a retention structure 100 comprising an open end portion118 to inhibit irritation of the lacrimal gland and an inward extension116 to inhibit contact with the caruncle of the eye.

FIG. 5I shows a retention structure 100 comprising an inward extension117 to inhibit contact irritation of lacrimal gland and an open endportion 118 to inhibit contact with the caruncle of the eye.

The retention structure 110 as described herein can be combined with oneor more of the support structure 120, the therapeutic agent 130 and thematrix 140 in many ways. When the retention structure 110 having the oneor more portions to inhibit irritation of one or more of the caruncle orthe lacrimal gland is placed, the support structure 120 can be locatedat one or more of a superior location under the upper lid, an inferiorlocation under the lower lid, an inferior temporal location under thelower lid, an inferior nasal location under the lower lid, a temporallocation under one or more of the upper lid or the lower lid, andcombinations thereof.

FIG. 5J shows an insert 100 comprising a retention structure 110 shapedwith an inward extension 117 to inhibit irritation of the lacrimal glandand an inward extension 116 to inhibit contact with the caruncle of theeye, in which the support structure 120 is located on the retentionstructure 110 so as to correspond with a superior placement under thesuperior eyelid.

The retention structures as described herein, for example with referenceto FIGS. 5A to 5J, may comprise a 3D shape elevational profile prior toplacement corresponding to the retention structure placed on a sphericalsurface having a radius of curvature corresponding to the eye of thepatient, and the retention structure can be configured to retainsubstantially the pre placement shape and resist deflection away fromthe pre placement shape.

FIG. 6A shows an insert 100 comprising a lentoid retention structure 110having an open end portion 118 to inhibit contact with the caruncle ofthe eye when placed on the eye with the support structure 120 comprisingthe therapeutic agent 130 placed on the inferior temporal location asdescribed herein. The open end portion 118 can fit many sizes of eyeswith one retention structure and may facilitate sizing and placement ofinsert 100. The open end portion 118 can be sized to inhibit contactwith one or more of the lacrimal gland or the caruncle, for example.

FIG. 6B shows an insert 100 comprising a circular retention structure110 having an open portion to inhibit contact with the caruncle of theeye when placed on the eye with the support structure 120 comprising thetherapeutic agent 130 placed on the inferior temporal location of theeye as described herein. The open end portion 118 can fit may sizes ofeyes with one retention structure and may facilitate sizing andplacement of insert 100. The open end portion 118 can be sized toinhibit contact with one or more of the lacrimal gland or the caruncle,for example.

FIG. 6C shows an insert 100 comprising a round retention structurehaving first support structure 120 comprising a first therapeutic agent130 at a first location corresponding to an inferior temporal locationof the eye and a second support structure 120B comprising a secondtherapeutic agent 132 at a second location corresponding to a superiorlocation of the eye.

FIG. 6D shows an insert comprising a round retention structure having anopen end and a first support structure 120 comprising a firsttherapeutic agent 130 at a first location corresponding to an inferiortemporal location of the eye and a second support structure 120Bcomprising a second therapeutic agent 132 at a second locationcorresponding to a superior location of the eye. The retention structuremay comprise end portions 119, and the end portions 119 may have a crosssectional dimension greater than the elongate portion of retentionstructure 110 so as to inhibit penetration of the epithelium and intothe conjunctival tissue of the eye, for example. Alternatively, the endportions 119 may comprise a cross sectional size similar to the elongateportions retention structure 110, for example when the cross sectionaldimension 112 of the elongate portion of retention structure 110comprises at least about 0.5 mm, for example.

The embodiments as described herein and in particular with reference toFIGS. 5A to 6D can be configured in many ways, and may comprise a 75degree, a 180 degree or a 360 degree drug release element, for example.The inserts can be fully coated or may comprise a 360 degree or greaterdrug release element as described herein, for example. In manyembodiments, the insert can be coated with a cushioning material, forexample a soft silicone or hydrogel.

Work in relation to embodiments suggests that it can be helpful to fitthe retention structure 110 to the patient, or identify an insert 100having an appropriately sized retention structure. The retentionstructure 110 of insert 100 can be identified based on measurement ofone or more of a circumference of the head of the patient, a dimensionbetween eyes of the patient, a depth of the upper formix, a depth of thelower formix, a distance extending between a lateral canthus and amedial canthus of the eye, a distance extending between a cul-de-sac ofthe eye and a limbus of the eye, a dimension of the orbit, or a formixdepth measured with a formicrometer. For example, a dimension of aphysical characteristic of a population of patients can be measured, andone or more inserts placed in each member of the population to determineempirically the size of the insert corresponding to the measureddimension such that a patient can be fit with the measured insert. Aformicrometer to measure formix depth and area is described in“Measurement of formix depth and area: a novel method of determining theseverity of formix shortening”, Kawakita et al., Eye (2009) 23,1115-1119. While non-limiting examples are shown in accordance withembodiments as described herein, a person of ordinary skill in the artcan determine many suitable patient measurements to fit retentionstructure 110 of insert 100 to an eye of the patient based on theteachings described herein.

The retention structures as described herein, for example with referenceto FIGS. 6 to 8, may comprise a 3D shape elevational profile prior toplacement corresponding to the retention structure placed on a sphericalsurface having a radius of curvature corresponding to the eye of thepatient, and the retention structure can be configured to retainsubstantially the preplacement shape and resist deflection away from thepreplacement shape.

FIGS. 7A and 7B show plan and side cross-sectional views, respectively,of an insert 100 comprising an outer retention structure 110 having aresistance to deflection to remain within the eye for an extended time.The insert 100 may comprise inclusions 131 of therapeutic agent 130contained within a matrix 140 as described herein. The matrix 140 maycomprise a soft material, for example a soft silicone, liquid, or othermaterial contained within the retention structure 110. The retentionstructure 110 may comprise a material having a higher durometer than thematrix material, for example. The retention structure 110 may comprise amaterial to inhibit release of the therapeutic agent, and a plurality ofholes 110H may extend through the retention structure to release thetherapeutic agent.

In many embodiments, the matrix 140 comprises a soft material, and theretention structure 110 comprises a coating placed on the soft matrixmaterial comprising the inclusions 131 of the therapeutic agent. Thecoating can be placed on the matrix in many ways and may comprise one ormore of a dip coating or a vapor coating. The coating may comprise oneor more of luminous vapor deposition of silicone in layers, or hydrogeldip coating, for example. A soft cushioning coating or other coating asdescribed herein can be provided over the surface of the retentionstructure.

The retention structure 110 can be configured to provide a resistance todeflection so as to maintain placement of the insert in the eye, forexample one or more of a deflection resistance or a hoop strength asdescribed herein. The thickness of and diameter of the retentionstructure can be dimensioned so as to provide the resistance todeflection.

FIGS. 7C and 7D show plan and side cross-sectional views, respectively,of an arcuate C-shaped insert comprising an outer retention structurehaving a resistance to deflection to remain within the eye for anextended time. The C-shaped insert may comprise many components of theinsert described above with reference to FIGS. 7A and 7B. The C-shapedinsert may comprise a resistance to inward deflection, for example aspring force, such that the insert can resist being urged inward by theeyelids so as to inhibit movement of the insert toward the cornea whenthe eye blinks. The C-shaped insert can be sized and provided withspring force so as to urge outward against the upper and lower formicesof the eye to retain the insert. Alternatively, the insert can be placedsubstantially in the upper formix or the lower formix and have itsforces directed at temporal and nasal directions, for example. Theinsert may comprise a gap distance extending between ends of the insert,and the gap distance can decrease slightly in response to inward forceof the eyelids and increase so as to urge the upper and lower formicesapart slightly.

The embodiments as described herein and in particular with reference toFIGS. 7A to 7D can be configured in many ways, and may comprise portionsconfigured with the drug release and may comprise a 75 degree, a 180degree or a 360 degree drug release element for example. The inserts canbe fully coated or may comprise a 360 degree or greater drug releaseelement, for example. In many embodiments, the insert can be coated witha cushioning material, for example a soft silicone or hydrogel.

FIG. 8A shows treatment 850 of a retention structure 110 of an insert100 to increase a resistance to deflection of the retention structure.The insert 100 can be placed in the eye 10 with the retention structure110 comprising a compliant configuration. The retention structure 110comprises a shape corresponding to the shape of the eye, and theretention structure 110 is treated. The shape of the compliant retentionstructure may correspond to the shape of the conjunctival sac and theone or more folds as described herein, for example. The retentionstructure 110 can be treated in many ways, for example with energy orwater of the eye to increase the resistance to deflection.

FIG. 8B shows in situ forming of a retention structure of an insertcomprising an in situ formable material. The insert may comprise a firstconfiguration having dimension 114A in an unloaded configuration priorto placement such as a diameter across as described above, and a secondconfiguration comprising a shorter dimension 114B and a longer dimension114C when placed in the eye as described above. When the insertcomprises the second configuration, the insert can initially exert aforce in response to deflection such that the retention structure exertsan outward force toward the formices of the conjunctiva. When the inserthas been left in the eye for an amount of time, the insert may be formedso as to comprise an in situ formed third configuration such that theinsert comprises shorter dimension 114D and longer dimension 114E. Whenthe insert is removed the insert may retain substantially the shape ofthe third configuration, for example. When the insert comprises theformed third configuration, the insert may resist deflection away fromshorter dimension 114D and longer dimension 114E. The in situ formedconfiguration may comprise one or more of many shapes such as an oval,an ellipse, a saddle, or combinations thereof, for example. The in situformed configuration may comprise at least a portion of retentionstructure 110 extending away from a plane corresponding to otherportions of the retention structure, for example when the in situ formedretention structure is placed on a planar surface with at least aportion extending away from the surface as described herein.

The in situ formable material may comprise one or more of polypropyleneor a known in situ formable material.

FIG. 8C shows a flowable material 140F placed on the eye to form atleast a portion of the insert 100.

The in situ formable insert can be formed in many ways. The in situformable insert can be formed by placing a liquid or flowable material140F on the conjunctiva 50 of the eye 10 at a location corresponding tothe intended location of the insert, for example away from the cornea 12along the cul-de-sac. The flowable material can be placed in many wayson the conjunctiva, for example along a portion of the cul-de-sac, alonga substantially arcuate path along a majority of the cul-de-sac, alongat least a portion of both cul-de-sacs, or in a C-shaped oval or othershape as described herein. The amount of flowable material placed maycomprise a predetermined amount, and the concentration of therapeuticagent in the flowable material 140F may comprise a predeterminedconcentration, such that the amount of flowable material placed on theeye comprises a predetermined amount of material and a predeterminedamount of therapeutic agent so as to release therapeutic amounts for anextended time as described herein. The liquid or flowable material 140Fmay comprise a therapeutic agent 130 and a support material that cancure to form a matrix, for example. The liquid or flowable material cansolidify so as to form the insert having one or more of the retentionstructure or the matrix as described herein. For example, the insert maycomprise the unitary insert comprising the matrix material having theself-loading resistance to deflection as described herein. The flowablematerial can be injected into the cul-de-sac of the eye and allowed tosolidify, for example.

Examples of flowable materials capable of solidifying on the eye arepublished in U.S. patent application Ser. No. 12/704,692, entitled “DrugDelivery Through Hydrogel Plugs”, Published as US2010/0209478A1, theentire disclosure of which is incorporated herein by reference andsuitable for combination in accordance with at least some embodimentsdescribed herein. The amount of flowable matrix material 140F placed onthe eye can be sufficient so as to provide an amount of therapeuticagent in accordance with embodiments as described herein, for example.Alternatively or in combination, the flowable matrix material 140F canbe shaped so as to provide the surface area of the matrix comprisingsolidified flowable material for sustained release for the extended timeas described herein. The flowable matrix material can be combined with aretention structure as described herein, for example combined with theretention structure before placement or after placement on the eye. Theflowable matrix material can be coated or provided in a retentionstructure or on a retention structure as described herein, for example.

FIG. 8D depicts syringe system 300 with barrel 302, needle hilt 303,needle 304 with rounded tip 306 having outlet 308 and plunger 310 withpusher 312. The amount of therapeutic agent placed can be sufficient soas to provide therapeutic amounts for an extended time as describedherein, for example with a substantial amount extra amount oftherapeutic agent removed from the eye upon completion of treatment asdescribed herein. A solution of hydrogel precursors 314 and therapeuticagent may be placed in barrel 302 and dispensed through needle 304 andout outlet 308. One embodiment of syringe system includes alternativeneedle with a hydrophobic coating that produces a high contact anglebetween the needle and precursor solution to assist forming drop and/orassist in leaving the solution after it is placed in the patient byvirtue of the resistance of the needle to spreading of solution. Theamount of therapeutic precursor material placed may comprise apredetermined volume of flowable material so as to provide apredetermined amount of therapeutic agent.

FIG. 8E depicts syringe system 300 being used to introduce hydrogelprecursors 314 into the cul-de-sac 53, for example into the formix 54,with the precursors being left in on or more of the cul-de-sac or theformix, for example. The precursors form covalent bonds with each otherto create a crosslinked hydrogel insert 100 as described herein. Theinsert 100 can swells as fluids are imbibed from its surroundings. Theintroduction of hydrogel precursors in a fluid state with subsequentformation of the hydrogel is referred to as in situ formation of thehydrogel because the hydrogel is created at the site of its intendeduse.

The hydrogel may contain linkage which gradually hydrolyze in thepresence of water at a predetermined rate, gradually sloughing off inthe patients tears. The hydrogel is composed substantially of water andpolyethylene glycol (PEG), widely considered an inert and biocompatiblematerial. Additional description of hydrogel materials and therapeuticagent delivery are available on the world wide web at the website ofOcular Therapeutix (ocutx.com).

The amount of therapeutic agent that be placed on the eye can be muchlarger than a punctual plug device, for example. In many embodiments,the flowable material 140F comprising the formulation is non-absorbable.

FIG. 9 shows a kit 600 comprising a plurality of retention structureshaving incrementally increasing sizes to determine a size of theretention structure to fit the patient. The kit may comprise a firstinsert having a first retention structure 110A having a first maximumdimension across such as a first diameter, a second retention structure110B having a second maximum dimension across such as a second diameter,a third retention structure 110C having a third maximum dimension acrosssuch as a third diameter, and a fourth retention structure 110Dcomprising a fourth maximum dimension across such as a fourth diameter,for example. The retention structures can be sized in many ways andcomprise a plurality of diameters, for example of 22 mm, 23 mm, 24 mm,25 mm, 26 mm, 27 mm, 28 mm, 29 mm, and 30 mm. When a retention structure110 among the plurality has been appropriately fit to the eye, an insert100 can be identified from among a plurality of inserts and placed inthe eye. When the insert 100 comprises support structure 120 the kit 600can be configured such that the first retention structure 110A comprisesfirst support structure 120A similar to support structure 120, thesecond retention structure 110B comprises second support structure 120Bsimilar to support structure 120, the third retention structure 110Ccomprises third support structure 120C similar to support structure 120,and the fourth retention structure 110D comprises fourth supportstructure 120D similar to support structure 120 of insert 100, forexample.

The ring structures of FIG. 9 may comprise a 3D shape elevationalprofile prior to placement corresponding to the retention structureplaced on a spherical surface having a radius of curvature correspondingto the scleral portion of the eyeball of the patient, and the retentionstructure of the kit may comprise 3D shape profiles corresponding to aplurality of radii Rb of the eyeball of the patient, for example radiusRb corresponding to 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27mm, 28 mm, 29 mm and 30 mm.

FIG. 10 shows a measurement apparatus 710 having markings 720 to measurea dimension of structure of the patient to determine a correspondingsize of the retention structure to fit the patient. The patient can bemeasured in many ways, and one or more measurements of the patient maycorrespond to the size of the retention structure that fits the patient.For example, a size of the palpebral fissure PF extending between thelateral canthus and medial canthus can be measured and may correspondsubstantially to the size of the retention structure to fit the patient.The dimension of the palpebral fissure can be measured with a ruler, forexample, and the size of the retention structure can be determined basedon the dimensions of the palpebral fissure. A nomogram can receive asinput the dimensions of the palpebral fissure and provide as output anidentification of the insert, such that retention structure forplacement on the patient can be identified based on the measured patientdimension. Based on the teachings described herein, a person of ordinaryskill in the art can determine empirically the correspondence betweenthe measured dimension of the patient and the size of retentionstructure such that the nomogram can be provided to identify the size ofthe retention structure based on the measured dimension of the patientsuch as the palpebral fissure.

Alternatively, the measurement apparatus 710 may comprise a curvedstructure sized to extend from a lateral canthus of the eye and a medialcanthus of the eye. The curved structure may comprise markingscorresponding to widths of a palpebral fissure extending between thelateral canthus and the medial canthus, for example.

FIG. 10A shows a measurement apparatus 750 to measure a depth of theconjunctival sac of the patient to determine a corresponding size of theretention structure to fit the patient. The measurement apparatus 750may comprise a plurality of indicia 760 to indicate a depth of theconjunctival sac. The plurality of indicia can be located at incrementaldistances from a distal end portion 752. The measurement apparatus 750comprises a handle 754. The handle and the end portion having themarkings can be transparent so that the user can easily visualize thetissue beneath the markings.

FIGS. 11A and 11B show a patient looking to a first side and a secondside, respectively, to measure a plurality of dimensions 1100 of the eyeto fit the retention structure 110 of insert 100 to the eye. Theplurality of measured dimensions 1100 of the eye may comprise a distance1100A from the limbus 14 to the lateral canthus when the patient looksnasally, for example. Alternatively or in combination, the plurality ofdimensions 1100 may comprise a distance 1100B from the limbus 14 to thecaruncle 59 when the patient looks nasally. The plurality of measureddimensions 1100 of the eye may comprise a distance 1100C from the limbus14 to the lateral canthus LC when the patient looks temporally, forexample. Alternatively or in combination, the plurality of dimensions1100 may comprise a distance 1100D from the limbus 14 to the caruncle 59when the patient looks temporally.

In many embodiments, the retention structure 110 and support structure130 can be visible to permit the user to see the insert to confirm thatthe retention structure is well placed in the eye, for example. Thefolds of conjunctiva may cover the retention structure to decreasevisibility. For example, the plica semilunaris may cover the retentionstructure near the caruncle and medial canthus so as to decreasevisibility of the portion of the retention structure extending acrossthe medial portion the palpebral fissure. However, in many embodimentsit can be beneficial to have at least a portion of the retentionstructure or the support structure less visible.

FIGS. 12A1 and 12A2 show plan and side views, respectively, of theinsert 100 having a therapeutic agent and at least one opticallytransmissive portion 100TR and at least one visible portion 100VI. Theoptically transmissive portion 100TR may comprise an opticallytransmissive material such as silicone, nylon, or suture material. Thevisible portion may comprise an optically visible material such as adark material, a colored material, a light colored material, afluorescent material, a light colored material, or combinations thereoffor the patient to see the insert when the lid is moved. The color ofthe insert may indicate the formulation or therapeutic agent, orformulation of therapeutic agent, for example.

The optically visible portion can be configured for placement under thelid. The optically transparent material can be configured to extendbetween the lids when placed on the eye.

The insert 100 comprises a first configuration 100C1 prior to placementand a second configuration 100C2 when placed in the eye, such that theinsert can deflect along the conjunctival sac.

FIGS. 12B1 and 12B2 show insert 100 comprising a second configuration100C2. The second configuration 100C2 comprises a superior inferiordimension across 100SI and a nasal temporal dimension across 100NT. Thenasal temporal dimension across 100NT can be greater than theinferior-superior dimension across 100SI. The second configuration 100C2comprises an anterior-posterior deflection 100AP corresponding toanterior-posterior deflection of the deflection of the insert 100 andretention structure 110 when placed in the eye.

The insert 100 and retention structure 110 can comprise manyconfigurations. The insert 100 and retention structure 110 may comprisea substantially uniform thickness extending substantially around acircumference of insert 100 in the first configuration 100C1.

FIGS. 13A1 and 13A2 show a support structure 120 configured to resistmovement away from the inferior temporal IT portion of the conjunctivalsac. The support structure 120 comprises a distance 126 sized to fit theIT portion of the conjunctival sac, and a first inclined surface offirst tapered end portion 122 and a second inclined surface of secondtapered end portion 124 opposite the first inclined surface. The firstinclined surface urges the structure toward the second inclined surfacein response to pressure of the lids and the second inclined surface ofsecond tapered end portion 124 urges structure 120 toward the firstinclined surface of first tapered end portion 122, such that movementaway from the IT portion of the conjunctival sac is inhibited inresponse to increased pressure of the lid at one or more of the temporallocation of the lid or the inferior location of the lid.

FIGS. 13B1 and 13B2 show insert 100 comprising second configuration100C2. The second configuration 100C2 comprises superior inferiordimension across 100SI and nasal temporal dimension across 100NT. Thenasal temporal dimension across 100NT can be greater than theinferior-superior dimension across 100SI. The second configuration 100C2comprises an anterior-posterior deflection 100AP corresponding toanterior-posterior deflection of the deflection of the insert 100 andretention structure 110 when placed in the eye. The support structure120 and retention structure 110 can rotate, such that the retentionstructure 110 and support structure 120 comprise a rotated configuration100C2R.

The support structure 120, the optically transmissive portion 100TR andoptically visible portion 100VI can be arranged on the insert 100 suchthat the optically transmissive portion 100TR is located near the nasalcanthus or the medial canthus and the optically visible portion 100VI iscovered by the upper lid or the lower lid. This allows the insert to beseen by the user to confirm the insert is placed on the eye and also todecrease visibility of the insert during normal gaze.

FIGS. 14A1 and 14A2 show plan and side views, respectively, of structure120 comprising a first structure 120S1 and a second structure 120S2spaced apart with distance 126 to maintain the first structure and thesecond structure in the inferior temporal location of the conjunctivalsac. The first structure 120S1 may comprise the first inclined surfaceof first tapered end portion 122 and the second structure 120S2 maycomprise the second inclined surface of second tapered end portion 124.The distance 126 can be sized to limit movement of the insert 100, andin accordance with dimension of transmissive portion 100TR and visibleportion 100V, such that the transmissive portion 100TR remainssubstantially in the canthus.

FIGS. 14B1 and 14B2 show the insert 100 placed along at least a portionof the conjunctival sac of an eye.

In many embodiments, structure 120 may comprise one or more structuresto retain the insert 100 with an intended orientation of thetransmissive portion 100TR and the optically visible portion 100VI.

FIG. 15 shows insert 100 comprising a C-shaped configuration withretention structure 110 comprising a first end and a second end.

FIG. 16A shows insert 100 comprising a therapeutic agent 130 of matrix140 and a second therapeutic agent 132 of a second matrix 142. FIG. 16Bshows a cross sectional view of an insert as in FIG. 16A. The matrix 140may comprise a first component and the matrix 140 may comprise a secondmatrix 142. The first matrix and the second matrix can be coupled to theretention structure 110, such that the retention structure extends alongthe matrix 140 and the second matrix 142. The first matrix may comprisesilicone and the second matrix may comprise silicone and the retentionstructure may extend between the first matrix and the second matrix withthe first matrix attached to the second matrix. In alternateembodiments, the first matrix may not be attached directly to the secondmatrix, for example.

FIG. 16C shows an insert 100 comprising extensions 125 to releasetherapeutic agent 130 from support structure 120. The extensions 125 canextend inward toward the pupil of the eye to release the therapeuticagent into the tear of the eye, for example when support structure isreceived in one or more folds of the conjunctiva as described herein.The extensions 125 may comprise a material suitable to receive thetherapeutic agent 130 from support structure 120 on a first end of theextension and release the therapeutic agent toward the pupil near asecond end. The extension 125 may comprise one or more of many materialsand may comprise silicone or hydrogel, for example. The supportstructure 120 may comprise matrix 140, and the matrix 140 may comprisesilicone and the extensions may comprise silicone so as to releasesilicone to the tear toward the pupil, for example.

FIG. 16D shows insert 100 comprising a retention structure 110comprising a matrix 140 containing a therapeutic agent 130. Theretention structure 110 may comprise inclusions of therapeutic agent 130as described herein and a matrix material to provide a resistance todeflection as described herein. For example, the matrix material maycomprise silicone and an inclusions of a prostaglandin embedded withinthe matrix. The retention structure 110 comprising the matrix materialcan be sized so as to provide a resistance to deflection as describedherein, and the therapeutic agent can be released from the surface ofthe retention structure 110.

FIG. 16E shows an insert 100 comprising a support structure 120 havingextensions 129 sized to release therapeutic agent 130 away from theretention structure 120.

FIG. 16F shows a side cross sectional view of the insert comprising thesupport structure having extensions to release therapeutic agent awayfrom the retention structure as in FIG. 16E. The therapeutic agent 130may be contained in matrix 140 having a surface area and volume sized torelease therapeutic amounts of the therapeutic agent for an extendedtime. The extensions 129 can extend between the retention structure 110and matrix 140 so as to position matrix 140 toward the tear of the eyeaway from the fold receiving the retention structure 110, such that thetherapeutic agent can be released to the tear from the surface of theretention structure 110 for the extended time.

FIG. 16G shows a support structure comprising a plurality of outwardextensions to increase a surface area of the matrix to release thetherapeutic agent. The therapeutic agent 130 may be contained in matrix140 having a surface area and volume sized to release therapeuticamounts of the therapeutic agent for an extended time. The extensions129 may comprise an extension of the matrix 140 and may extend away fromthe retention structure 110 to release the therapeutic agent to the tearfrom the surface of the retention structure 110 for the extended time.At least a portion of the extensions 129 can be directed inward towardthe pupil of the eye.

FIG. 17A shows components of a mold 1700 to make the insert 100comprising a first component 1710 and a second component 1720. The firstcomponent 1710 may comprise a first channel 1712 sized to form a firstportion of support structure 120 and a first channel 1714 sized toreceive a first portion of preformed retention structure 110. The secondcomponent 1720 may comprise a second channel 1722 sized to form a secondportion of support structure 120 and a second channel 1724 sized toreceive a second portion of preformed retention structure 110. The firstcomponent and the second component can be placed in contact with thefirst channels aligned with the second channels. In many embodiments,the preformed retention structure may be threaded through a spacer, forexample a small silicone bead, sized to place the retention structure110 near a central portion of the channel defined by first channel 1712and second channel 1722. This placement of the preformed retentionstructure away from the surface of the first channel 1712 and thesurface of the second channel 1722 can increase smoothness of thesupport structure 120 formed with the first channel and the secondchannel.

FIG. 17B shows the mold as in FIG. 17A having a preformed retentionstructure placed in the mold configured for injection of a flowablematerial. The flowable material can be injected into the mold 1700 andcured to form insert 100. The flowable material may comprise thetherapeutic agent, such that the support structure 120 comprises thetherapeutic agent. Alternatively, the matrix comprising the therapeuticagent may comprise a solid matrix that can be placed in the channelssized to form the support structure 120, and the flowable materialinjected around the preformed solid matrix. For example, the matrix maycomprise a preformed silicone matrix containing the therapeutic agentplaced in the mold and the flowable silicone material injected aroundthe silicone matrix.

In many embodiments, the inclusions of the therapeutic agent are formedin a matrix with a method of manufacturing the therapeutic device. Themethod comprises dissolving particles of a therapeutic agent in one ormore of a first component comprising vinyl or a second componentcomprising a catalyst and a hydride. The one or more of the firstcomponent or the second component comprises a solvent to dissolve thematrix. The first component and the second component are combined toform a curable material comprising the therapeutic agent dissolved inthe solvent. The solvent is removed from the curable material to forminclusions of the therapeutic agent in a matrix comprising the firstcomponent cured with the second component.

The matrix comprising the inclusions of the therapeutic agent can becoupled to the retention structure in many ways. For example, thecurable material comprising the therapeutic agent dissolved in thesolvent can be placed in the mold 1700 and cured around the retentionstructure 110 to form the matrix comprising the first component curedwith the second component. Alternatively, the matrix comprising thefirst component cured with the second component can be formed, placed inthe mold and a flowable material injected around the matrix.

FIG. 17C shows a mold 1700 to make the insert comprising a firstcomponent 1710 and a second component 1720, in which the mold comprisesa first channel 1712AC to inject a first flowable material comprising afirst therapeutic agent 130 and a second channel 1712BC to inject asecond flowable material comprising a second therapeutic agent 132. Thefirst channel 1712AC extends to a channel 1712 comprising a portion1712A having a size and shape corresponding to the area and volume ofthe first matrix 140 comprising the first therapeutic agent. The secondchannel 1712BC extends to channel 1712 comprising a portion 1712B havinga size and shape corresponding to the area and volume of the secondmatrix 142 comprising the second therapeutic agent 132. A separator 120Scan be placed in the mold prior to injection of the one or more flowablematerials comprising the therapeutic agent so as to separate theportions. The separator 120S can hold the retention structure 110, forexample a suture, away from a surface of the mold such that theretention structure can be embedded away from a surface of the matrix.

FIG. 17D shows a mold to make the insert comprising a first component1710 and a second component 1720, in which the mold comprises a firstchannel 1712AC to inject a first flowable material comprising a firsttherapeutic agent 130 and a second channel 1712BC to inject a secondflowable material comprising a second therapeutic agent 132 and a thirdchannel 1712CC to inject a third flowable material substantially withouttherapeutic agent. The first channel 1712AC extends to a channel 1712comprising a portion 1712A having a size and shape corresponding to thearea and volume of the first matrix 140 comprising the first therapeuticagent. The second channel 1712BC extends to first channel 1712comprising a portion 1712B having a size and shape corresponding to thearea and volume of the second matrix 142 comprising the secondtherapeutic agent 132. The third channel 1712CC extends to first channel1712 comprising a portion 1712C having a size and shape corresponding tothe retention structure 110. The separator 120S can be placed in themold prior to injection of the one or more flowable materials comprisingthe therapeutic agent so as to separate the portions. For example, thefirst separator 120S1 can separate the first portion from the secondportion; the second separator 120S2 can separate the second portion fromthe third portion; and the third separator 120S3 can separate the thirdportion from the first portion. The separators may comprise materialssimilar to the portions similar to a cured form of the flowablematerial, such that the portions can bond to the separators when cured.For example, each of the portions and each of the separators maycomprise silicone elastomer.

FIGS. 17E and 17F show a spherical mold 1700 having an oval shapedchannel to make the insert in which the mold comprises a first lowercomponent 1710 comprising a convex spherical surface and a second uppercomponent 1720 comprising a concave spherical surface to nest with theconvex spherical surface. Although a convex spherical surface is shown,the convex surface may comprise one or more of a toric surface, a conicsurface, a spherical surface, a cylindrical surface, or a sphericalsurface. The concave surface may comprise a surface profile so as tocorrespond and nest with the convex surface and may comprise one or moreof a toric surface, a conic surface, a spherical surface, a cylindricalsurface, or a spherical surface. The convex surface may comprise thelower surface and the concave surface may comprise the upper surface ofthe mold. Each of the convex spherical surfaces may correspond to theradius of curvature of the eyeball comprising the sclera. Manycomponents and channels of the mold are similar to FIGS. 17C and 17D.The channels of the mold can be formed on the spherical surface of themold so as to provide the 3D shape profile of the insert. The mold maycomprise one or more channels corresponding to first dimension 114A1 andsecond dimension 114A2 of the insert, and the oval dimensions can beplaced on the convex spherical surface and the concave sphericalsurface, so as to form the insert having 3D shape profile comprising thefirst sag height and the second sag height and resistance to deflectiontoward a plane as described herein.

FIG. 17G shows a spherical mold 1700 having an oval shaped channel onthe spherical surface to make the insert in which the mold comprises afirst channel to inject a first flowable material comprising a firsttherapeutic agent, a second channel to inject a second therapeutic agentand a third channel to inject a flowable material without substantialtherapeutic agent as described herein.

FIG. 18 shows a manufacturing process 1800 in accordance withembodiments. At a step 1820 the suture material is stress relieved inthe oven. At a step 1825 the suture is thermoformed into a ring. Thesuture can be formed into a ring by wrapping the suture around a mandrelwith a diameter of approximately 25 mm and heated to about 150° C. forone hour to heat-set the ring shape. At a step 1830 the ring is cut. Thesuture is trimmed to the correct length and the ends thermally weldedtogether to form the suture ring.

At a step 1805 the drug is mixed with part A of the silicone. Forexample, a prostaglandin comprising bimatoprost can be mixed into themedical grade silicone. At a step 1810 part A and part B of the siliconeare mixed. At a step 1815 a syringe is filled with the drug formulation.

A step 1835 ring spacers are overmolded. At step 1840 spacers are placedon rings. At a step 1845 rings are fused. At a step 1850 joint integrityis inspected.

At a step 1860 rings are overmolded. The formed suture can be overmoldedwith medical grade silicone and cured at elevated temperature to formthe silicone segments. At a step 1865 the rings are deflashed/demolded.At a step 1870 the overmold quality is inspected. At a step 1875 ringsare placed in 70% isopropanol at room temperature for 5-60 minutes. At astep 1880 the rings are dried at room temperature for at least about 30minutes. At a step 1885 the rings are placed in a vacuum oven at 40degrees Centigrade. At a step 1890 the insert undergoes finalinspection. At a step 1895, the insert is packaged and subsequentlysterilized by e-beam radiation prior to arrival at the medical facility.

The method 1800 provides a non-limiting example of a method ofmanufacturing a therapeutic insert in accordance with at least someembodiments as described herein. A person of ordinary skill in the artwill recognize many variations and adaptations based on the teachingsdescribed herein. For example, the steps of the method can be performedin any order, and the steps can be deleted, or added, and may comprisemultiple steps or sub-steps based on the teachings described herein.Further the method can be modified so as to provide any insert asdescribed herein and so as to provide one or more of the functions anyone or more of the inserts as described herein.

Verification Processes and Release Testing

Machinery used during the manufacturing process that can influence theperformance of the device can be tested to verify that it meetsappropriate specifications and tolerances. Machinery included in thistesting may include the refrigerator in which the prostaglandincomprising bimatoprost is stored, the mixer in which the prostaglandincomprising bimatoprost is mixed with the silicone, and the packagingsealer machine. Additionally, appropriate equipment such as ovens andbalance can be kept within calibration.

Prior to release of clinical product, all lots will be tested byappropriate statistical sampling for mechanical integrity, sterility,drug content uniformity, drug purity, elution profile, and residualchemicals to ensure that the clinical lots are consistent with theproduct specification.

Drug Loading and Dosing

The therapeutic agent can be provided in many ways as described herein.In many embodiments, an amount of the therapeutic agent is provided witha matrix comprising a support material and the therapeutic agent. Theamount of therapeutic agent contained in the matrix may comprise fromabout 0.1% to about 50% of the matrix. Table 3 lists amounts of drugthat can be loaded on the insert in accordance with embodiments, and theamount can be higher, or lower than the values shown in Table 3.

The inserts as described herein can be combined with the matrix asdescribed herein in many ways. The insert may comprise one or moreeluting elements. For example one eluting element having an arc lengthof 75 degrees, two eluting elements of 75 degrees each, or a singleeluting elements extending substantially 360 degrees around the ring.The largest cross sectional dimension of the eluting element can be adiameter within a range from about 0.5 to 1 mm, for example. The surfacearea of the eluting structures can be compared, for example with aratio, and the volume of the eluting structures available to storetherapeutic agent can be compared.

The amount of therapeutic agent may comprise about 4.4 mg (4,400 ug),for example with 7% therapeutic agent loaded onto a silicone matrix.With 50% loading, the amount of therapeutic agent can be about 7×greater, for example about 30 mg.

The amount of therapeutic agent loaded on insert 100 can besubstantially greater than needed to treat the patient for an extendedtime. For example, with 4.4 mg of prostaglandin comprising bimatoproston an insert, the amount released for 6 months of treatment can be about0.4 mg so as to provide at least about 3 ug per day, such that about 90%of the therapeutic agent may remain on insert when the insert is removedupon completion of treatment. The insert comprising excess storage ofthe therapeutic agent can provide for release of therapeutic agentwithin a therapeutic window above the minimum effective release rate andbelow a rate of release corresponding to potential side effects. Theamount of excess therapeutic agent can vary and may comprise one or moreof at least about twice the amount to be released to the eye over theextended time, at least about three times the amount to be released tothe eye, at least about four times the amount to be released to the eye,or at least about five times the amount to be release to the eye, forexample.

The drug release structure as described herein can be configured in manyways to release the therapeutic agent, for example with one or more of amatrix, a matrix surface area, a reservoir, a reservoir chamber, a pump,an osmotic pump, or a diffusion mechanism, and combinations thereof.Examples of amounts of therapeutic agent as described herein that can berelease from the insert placed on the eye include at least about 3 ugper day of therapeutic agent released for an extended time of at leastabout 60 days. The therapeutic agent may comprise a prostaglandin suchas bimatoprost, and at least about 3 ug of prostaglandin such asbimatoprost can be released each day for at least about 60 days. Thetherapeutic agent may comprise a prostaglandin such as bimatoprost, andat least about 4 ug of the prostaglandin such as bimatoprost can bereleased each day for at least about 60 days, for example. Thetherapeutic agent may comprise a prostaglandin such as bimatoprost, andthe amount of therapeutic agent released each day can be within a rangefrom about 5 ug to about 9 ug for at least about 60 days. Thetherapeutic agent may comprise a prostaglandin such as bimatoprost, andthe amount of therapeutic agent released each day for an extended timecan be within a range from about 5 ug to about 9 ug. The extended timeis within a range from about 120 days to 180 days, for example.

TABLE 3 Therapeutic Agent Loading and Surface Area Mono Mono Duo DuoSilicone - Silicone - Silicone - Design Variable v. 1.0 v. 2.0 v. 1.0 v.2.0 Suture #1 Suture #2 Suture #3 # eluting segments 1 1 2 2 1 1 1Largest diameter of 1 mm 1 mm 1 mm 1 mm 0.5 mm 0.75 mm 1 mm elutingstructure Ratio of surface 1.0 1.5 2.0 3.0 2.7 4.0 5.3 areas (47.9 mm²)(72.9 mm²) (95.7 mm²) (145.8 mm²) (128.3 mm²) (192.5 mm²) (256.6 mm²)Ratio of volume 1.0 1.6 2.0 3.2 1.5 3.5 6.1 (10.4 mm³) (16.6 mm³) (20.9mm³) (33.2 mm³) (16.0 mm³) (36.1 mm³) (64.2 mm³) Geometry of eluting ArcArc Double Arc Double Arc Circular Circular Circular structure (75°)(110°) (75° × 2) (110° × 2) (360°) (360°) (360°) Drug loading 7% 7% 7%7% 7% 7% 7% (bimatoprost) (~700 μg) (~1162 μg) (~1463 μg) (~2324 μg)(~1120 μg) (~2527 μg) (~4494 μg) Silicone durometer 10A 10A 10A 10A 10A10A 10AMechanism of Action—Exemplary Prostaglandin—Bimatoprost

While many therapeutic agents can be used, many embodiments comprise aprostaglandin such as bimatoprost as the therapeutic agent. The insertcan provide controlled drug delivery to the eye, while ensuring that theamount of drug delivered to the eye is safe. Bimatoprost itself is aprostamide, a synthetic structural analog of prostaglandin with ocularhypotensive activity. This prostamide is believed to lower intraocularpressure (IOP) in humans by increasing outflow of aqueous humor throughboth the trabecular meshwork and uveoscleral routes. The insert can beplaced on the surface of the eye, with silicone eluting an amount ofmedication per day. When used clinically, the efficacy of the insert canextend to 180 days or more, after which the insert be replaced by a newinsert containing an additional dose of bimatoprost.

Instructions for Use

The insert can be provided as a component of a kit, in which the kitcomprises the insert and instructions for use. For example, the kit 600may comprise the plurality of retention structures, an insert, and theinstructions for use. The instructions for use may include theinstructions listed below, for example.

The insert should be maintained at room temperature in an area free ofenvironmental extremes. The storage location at the clinical site musthave restricted access available only to study personnel

Procedure: The eyelids will be pulled back by the doctor's glovedfingers and, using forceps, a surgical spear (e.g. Weck-cel) and/or thedoctor's gloved fingers, the Insert will be placed in the upper andlower formices. Once the Insert is in place, given its ring-shapedskeleton it is anticipated that the eyelids will keep the Insert inplace:

The ocular insert is first placed by the doctor in the upper formixusing forceps, a surgical spear (e.g. Weck-cel) and/or the doctor'sgloved fingers.

The ocular insert is next placed by the doctor in the lower formix usingforceps, a surgical spear (e.g. Week-cel) and/or the doctor's glovedfingers.

The physician examines the placement of the insert. The blue suture canbe seen in the nasal corner of the eye.

The instructions for use may be used with a clinical study, andinstructions appropriate to the study provided.

The Investigator, or designee, may be responsible for keeping currentand accurate records of the Inserts dispensed and implanted. The studyinserts can be stored in a secure area in order to prevent unauthorizeddistribution. The investigational insert may be inserted only involunteers entered into the study, in accordance with the conditionsspecified in the Protocol.

The Insert is supplied sterile to the clinical site.

When the study is completed or terminated by the Sponsor, all unusedstudy inserts may be returned to the Sponsor (or its authorizedrepresentative), or destroyed under the direction of the same. TheSponsor, or designee, will verify study Insert accountability andcomplete the Product Return Shipment Form. All product accountingprocedures can be completed before the study is considered completed.The inserts can be intended for one-time use only.

EXPERIMENTAL

Initial studies have been conducted to determine dimensions andmaterials suitable for use with insert 100 comprising retentionstructure 110 and support structure 120. The following non-limitingexamples show insertable devices and methods in accordance withembodiments as described herein.

Example 1 Initial Experiments with Test Devices

Inserts have been constructed in accordance with the teachings describedherein. The inserts 100 comprised a ring shaped retention structure 110composed of a 4-0 nylon suture and a silicone support structure 120.Initial studies suggested that the first inclined surface of the firsttapered end portion 122 and the second inclined surface of the secondtapered end portion 124 can provide improved comfort. Additional insertshaving the inclined surfaces were constructed, and the test inserts wereplaced in the eyes of one human subject for approximately 29 days andwell tolerated.

FIG. 18A shows an image of the insert 100 placed on an eye with theretention structure 110 under a fold of bulbar conjunctiva comprisingthe plica semilunaris PS adjacent the caruncle 59 as described herein.The eye and retention structure are shown with the patient lookingforward and a first separation distance extending between the limbus 14and the retention structure 110.

FIG. 18B shows an image of the insert placed on the eye as in FIG. 18Awith the eye looking temporally so as to expose the insert from underthe fold 56F of bulbar conjunctiva 56 comprising the plica semilunarisand such that the retention structure slides along the bulbarconjunctiva so as to provide a second separation distance between thevisible portion of retention structure 110 and the limbus. The secondseparation distance corresponds to at least about twice the firstseparation distance. The separation distance from the limbus 14 of theeye to the visible portion of the retention structure 110 has increasedsubstantially as compared with the patient looking forward.

FIG. 18C shows an image of the insert placed on an eye with theretention structure extending under a fold 56F of bulbar conjunctiva 56.The retention structure 110 fits under fold 56F.

Example 2 Experiments with a Population of Test Subjects

Additional experiments were conducted with additional volunteers havinginserts placed in their eyes. These studies indicated varying resultsand that the sizing of the ring shaped structure to the size of the eyecan be helpful.

FIGS. 19A to 19F show placement locations of the support structurecomprising silicone elastomer coupled to the ring shaped retentionstructure as described herein. The inserts were placed on human eyes andcomfortably retained on the eyes for several days at the locationsshown. The silicone elastomer support structure comprised a maximumcross-sectional diameter of about 1.5 mm and a length of about 12 mm.The retention structure comprised a 4-0 polypropylene suture sized tofit the wearer as described herein. The subjects were fit to a 24, 26 or28 mm retention structure as described herein, and the support structurecomprising silicone was placed substantially as shown in the figures,although in some instances the insert rotated at least partially aroundthe pupil of the eye subsequent to placement.

FIG. 19A shows an insert placed in the right eye (hereinafter “OD”) andthe support structure 120 worn at an inferior temporal location with theretention structure 110 sized to fit within conjunctival folds asdescribed herein.

FIG. 19B shows an insert placed in the left eye (hereinafter “OS”) andthe support structure 120 worn at a temporal location with the retentionstructure 110 sized to fit within conjunctival folds as describedherein.

FIG. 19C shows an insert placed in the right eye OD and the supportstructure 120 worn at an inferior location with the retention structure110 sized to fit within conjunctival folds as described herein.

FIG. 19D shows an insert placed in the right eye OD and the supportstructure 120 worn at a superior location with the retention structure110 sized to fit within conjunctival folds as described herein.

FIG. 19E shows an insert placed in the left eye OS and the supportstructure 120 worn at an superior location with the retention structure110 sized to fit within conjunctival folds as described herein. Thissubject started with the support structure placed within the inferiorsac of the eye and retention with the lower lid was less than ideal,possibly related to a loose lower lid of the subject. The insert wassubsequently placed along the superior sac and well retained with thesupport structure under the upper lid.

FIG. 19F shows an insert placed in the left eye OS and the supportstructure 120 worn at nasal location near the caruncle with theretention structure 110 sized to fit within conjunctival folds asdescribed herein.

Experiment 3 Measurements of Resistance to Deflection

While the resistance to deflection of the insert can be measured in manyways, the resistance to deflection based on self-loading deflection ofthe insert can be performed readily with simple test equipment. Theinsert can be held horizontally on one end and the angle of deflectionof the insert away from horizontal based on gravity can be measured.

FIG. 20A shows measurement self-loading deflection of a retentionstructure of an insert. The insert can be held horizontally on one endand the angle away from horizontal measured so as to determine theself-loading resistance to deflection.

The self-loading resistance to deflection of several ring structures wasmeasured. Each ring structure had a 26 mm diameter. Rings made of 3-0Prolene, 4-0 Prolene, 5-0 Prolene, 3-0 Nylon, 4-0 Nylon, 5-0 Nylon,durometer 30A silicone and durometer 50A silicone were measured. Animage of each ring was taken and software (ImageJ, NIH freeware forimage processing/measurements) was used to measure the angle ofdeflection for each ring. Three ring samples were measured for eachmaterial and the self-loading angle of deflection averaged for each ofthe measurements. The results of the measurements are shown in Table 4.

TABLE 4 Self-Loading Angle of Deflection Description of Ave Angle RingAngle 1 Angle 2 Angle 3 Deflection 3-0 Prolene 13 12 12 12 4-0 Prolene12 14 12 12 5-0 Prolene 11 25 15 17 3-0 Nylon 12 8 6 8 4-0 Nylon 18 18 012 5-0 Nylon 21 14 15 17 30A silicone 83 82 90 85 50A silicone 67 52 6060

The Prolene and Nylon sutures provided greater resistance to deflectionthat silicone based on the measured self-loading deflection. The nylonsutures had average angles of deflection of 8 degrees, 12 degrees and 17degrees for the 3-0, 4-0 and 5-0 sutures, respectively.

The Prolene sutures had average angles of deflection of 12 degrees, 12degrees and 17 degrees for the 3-0, 4-0 and 5-0 sutures, respectively.The durometer 30A silicone has a self-loading deflection angle of about85 degrees and the harder 50A silicone has a self-loading deflectionangle of about 60 degrees.

This self-loading deflection data can be combined with retention of theinserts as described herein to determine the resistance to deflection soas to retain the insert in the eye. This data indicates that aself-loading deflection of less than about 60 degrees can providesufficient resistance to deflection so as to retain the insert in theeye. The measurable self-loading deflection also indicates that theretention structure can move and deflect so as to change shape andprovide comfort to the patient.

Experiment 4 In Situ Forming of the Retention Structure

FIG. 21 shows an insert as described herein removed from an eye. Theinsert initially comprised a circular retention structure comprising apolypropylene suture and was placed in an eye for a plurality of days soas to in situ form the retention structure. The in situ formedconfiguration comprised a non-planar oval shape when placed on a flatsurface. The in situ formed configuration comprises at least a portionof retention structure extending away from a plane corresponding toother portions of the retention structure. The in situ formed retentionstructure is shown placed on a planar surface with at least a portionextending away from the surface.

Experiment 5 Measurement of Eyes to Determine Sizes of the RetentionStructure

FIG. 22 shows a digital image of a human eye measured with a measurementapparatus as described herein. The patient can be asked to look down,and the instrument inserted at least partially into the conjunctival sacto measure a distance from the formix of the eye to the limbus of theeye with the patient looking down. The measured distance can be used todetermine a size of the retention structure to be placed in the eye, forexample and initial size identified from among a plurality of sizes.

Additional experiments are contemplated to determine appropriate sizingof the retention structure based on measurements of the patient, forexample as described herein.

Experiment 6 Test Devices Loaded with Therapeutic Agent

Test devices comprising a ring shaped retention structure comprising anylon suture and a support structure 120 having inclined surfaces wereplaced in an eye of a subject. The support structure comprised atherapeutic agent contained in a silicone matrix. The silicone matrixcomprised inclusions of the therapeutic agent as described herein, andthe therapeutic agent comprised a prostaglandin. The silicone matrixcomprised NuSil Med 4810 and the amount prostaglandin comprised about 2%bimatoprost. The cross-sectional diameter of the support comprising thematrix was about 1 mm and extended about 90 degrees around the ringshaped suture with the suture extending there through. The amount oftherapeutic agent within the matrix can be increased with additionalstudies and embodiments, for example to within a range from about 5-10%prostaglandin such as bimatoprost.

FIG. 23 shows a graph of IOP over time for a patient having an insertplaced on one eye and a control eye for at least about 1 month. The ringwas inserted in the right eye (OD) and the IOP decreased from about 22mm Hg to within a range from about 15 to 18 mm Hg to about 28 dayspost-op. The IOP of the untreated left eye (OS) remained substantiallyconstant and within a range from about 19 mm Hg to about 22 mm Hg. Thetherapeutic agent comprised a prostaglandin, bimatoprost, and theestimated amount released per day started at approximately 22 ug/day anddecreased to approximately 1 ug/day. The corresponding amount per dayfor drops to the eye of the therapeutic agent is approximately 9 ug/day.

Experiment 7 Evaluation of Patient Response to Insert Devices

FIG. 24A shows a tested insert comprising a suture ring and a single 75degree silicone band on the suture ring. The suture was made ofpolypropylene (prolene 4-0), having a nominal cross-section 0.150 mm.The silicone band was composed of medical grade silicone having adurometer of 10 A (Shore A) and a cross-sectional diameter 1.0 mm andextended over the suture.

FIG. 24B shows a tested insert comprising a silicone ring without asupporting suture. The silicone ring was composed of medical gradesilicone having durometer 10 A. The silicone ring comprised across-sectional diameter of 0.5 mm.

FIG. 24C shows a tested insert comprising a suture ring and two opposing75 degree silicone bands on the suture ring. The suture material andsilicone material were the same as the insert in FIG. 24A.

FIG. 24D shows an insert suitable for testing comprising an inner suturering covered with soft silicone around a 360 degree circumference. Thesuture may comprise a prolene (4-0) or a nylon (4-0) suture, each havingcross-sectional diameter of 0.150 mm. The silicone can be medical gradesilicone having a durometer within a range from about 10 A to about 50A, for example. The cross sectional dimension of the silicone can bewithin a range from about 0.25 mm to about 1.5 mm, for example within arange from about 0.5 mm and 1.0 mm.

Clinical testing of the insert shown in FIGS. 24A to 24C has shown thatthe deflection resistance provided by the suture material, which maycorrespond to hoop strength of the suture, can substantially increaseretention in human subjects. Testing of the insert comprising the sutureshown in FIG. 24A showed that seven of ten subjects could retain thering comfortably for four weeks. However, for the insert comprisingdurometer 10 A silicone without the suture as shown in FIG. 24B, onlytwo of ten test subjects were able to retain the ring for 10 days. Thedurometer 10 A silicone comprises a much softer material having a muchlower resistance to deflection, which may correspond to hoop strength,than the durometer 30A silicone. For the insert having two silicon bandsas shown in FIG. 24C, five of seven subjects were able to retain thering comfortably at three weeks and the study was ongoing at week three.

Experimental testing of the insert shown in FIGS. 24A to 24C has shownthat a mucus can form around the exposed suture material of theembodiments of FIGS. 24A and 24C having a diameter of about 0.15 mm, andthat relatively little mucus may form around the larger silicone portionof these inserts having a diameter within a range from about 0.5 to 1.0mm, for example. The cushioning provided by the soft silicone materialover the stiff suture material may also decrease mucus formation. Theaccumulation of mucus on the retention structure may decrease clearanceof mucus from the eye. As the decreased accumulation of mucus may berelated to increased biocompatibility of a plurality of inserts wornsuccessively for several years, the larger diameter of the soft siliconeportion over the suture may provide improved biocompatibility.

The insert may comprise at least portion configured to inhibit mucousformation, and the at least a portion can be configured for placementnear the medial canthus where mucous can accumulate in the eye. The atleast a portion may comprise one or more of a cross-sectional size of atleast about one half of one mm, a lubricous coating, a soft material, orcombinations thereof, for example.

Additional clinical studies have been conducted with silicone insertssimilar to FIG. 24B having a Shore A durometer of 10 or a Shore Adurometer of 50. For the inserts comprising a Shore A durometer of 10,four eyes were tested and only one retained the insert which was removedafter about one week. For the inserts comprising a Shore A durometer of50, six eyes were tested and only two retained the insert which wasremoved after about one week. These data indicate that the retentionstructure as described herein, for example with reference to FIGS. 24Aand 24C provides improved retention of the insert. Alternatively or incombination, a material more rigid than durometer 50 A can be used toform a unitary insert such that the more rigid material provides theresistance to deflection and the drug delivery matrix as describedherein. For example, a unitary ring as described herein with referenceto FIG. 24B can be manufactured with a durometer 80 A silicone loadedwith therapeutic agent, such that the silicone drug delivery matrixprovides the resistance to deflection and release of therapeutic agentas described herein.

Experiment 8 Clinical Study to Determine Safety, Comfort and Retentionof Ocular Insert without Bimatoprost (Placebo Device) in Humans

An open-label, single arm exploratory study to assess the comfort andretention of the ocular insert as described herein in healthy volunteerstook place. During the study, an ocular insert without drug was placedin the eyes of 10 volunteers for up to 28 days. The results of the studyshowed the insert to be safe, comfortable and well-retained over anextended period of time. Following is a detailed summary of the studyand its results:

Objectives:

1. To determine the safety profile of the ocular insert.

2. To determine comfort of the ocular insert.

3. To determine whether the ocular insert can be retained in theformices over an extended period of time.

Study Design:

Up to 20 healthy volunteers, between the ages of 21-65 (mean 45.1 years)could be enrolled in the study and monitored for up to 28 days whilewearing the insert in one eye. Safety, comfort and retention, as well asfollow-up on any adverse events were tracked and recorded on follow-upvisits on days 0, 1, 3, 7, 14, 21 and 28. A second enrollment periodtook place for a small subset of subjects who participated in the firstenrollment period of the study. In the second enrollment period theinsert was placed for up to 7 days in order to determine comfort andretention while placing the insert at a different orientation from theone used in the first enrollment period. Follow-up visits were on days0, 1, 3, and 7.

Description of Insert:

The ocular insert was a ring-shaped structure made of polypropylene, acommercially available non-absorbable suture material available underthe trade name Prolene™, manufactured by Johnson & Johnson Ethicon. Thestructure was coated in sections with medical grade silicone provided byNuSil Silicone Technology, and has a diameter of 20 to 28 mm (severalsizes of the insert are available) and the cross-sectional diameter ofthe ring varied from about 0.05 mm (7-0 suture) to about 0.20 mm (3-0suture). In this study, no drug was put into the ocular insert.

Criteria for Evaluation:

1. Safety: Biomicroscopy, slit-lamp photography and visual acuityexaminations took place, as well as follow-up on any adverse events atbaseline and during all follow-up visits.

2. Retention: On all follow-up visits, subjects were examined todetermine the presence of the Insert in the eye.

3. Comfort: On all follow-up visits, subjects were also asked to fillout a comfort questionnaire, in which they were requested to mention indetail any physical or emotional discomfort felt while wearing theocular insert.

Results:

For 10 subjects enrolled in the study since safety, comfort andretention outcomes were deemed to be sufficient to guide the researchand development. Subjects were aged 23-63 (mean 45.1 years) and included4 males and 6 females.

Eight out of 10 subjects completed the study and 28 day follow-upperiod. In two of the subjects the Insert was not retained for more than4 days.

Safety Conclusions: The results of the study show that the ocular insertis safe. Safety related events were as follows:

No Serious Adverse Events occurred in the study.

One adverse event occurred in subject HSG 003. In this subject,conjunctival redness went from none to moderate between baseline andday 1. Although redness begun to resolve over the following week it wasstill noticeable at day 7 and therefore the Insert was removed andreplaced with a smaller diameter Insert, which was well retained andcomfortable for the duration of the study without any adverse events.

The majority of participants had mild conjunctival redness and/or mucuscollection which did not qualify as adverse events (2 grades of changefrom baseline). All instances were intermittent in nature, did not causediscomfort to the subjects and did not require any treatment

Retention Conclusions: In 8 out of 10 subjects the insert was retainedfor the entire duration of the study. In 2 (RS 008 and TZA 007) of these8 subjects the Insert was repositioned between day 2 and day 3 so thesilicone band was placed in the upper formix.

Comfort Conclusions: Data from the comfort questionnaires, comparingoverall comfort of study eye (SE), in which the ring was inserted, andcontrol eye (CE) in which there was no Insert during study visits

Discomfort values were at their highest immediately after insertion, andgradually declined until stabilizing on a value reasonably close to thelevel of discomfort reported in the control eye.

The second, 7-day enrollment period demonstrated that for most patients,the optimal orientation for maximal retention and comfort was given whenplacing the silicone part of the ring in the upper formix of the eye

Overall Conclusions:

The study, designed to determine safety, retention and comfort of theocular insert without drug for up to 28 days, showed that the Insert wassafe, well retained and comfortable. These conclusions are based onmonitoring of adverse events, the high percentage of retention andreports by patients of a high level of comfort, which increased overtime.

The Protocol and Informed Consent Form (ICF) were reviewed and approvedby an Institutional Review Board (IRB), who was also kept informed ofany serious adverse events and any amendments to the protocol.

The study was performed in accordance with the recommendations guidingphysicians in biomedical research involving human subjects adopted bythe 18th World Medical Assembly, Helsinki, Finland, 1964 and lateramendments.

Experiment 9 Evaluation of Inserts Shaped In situ

FIG. 25 shows in situ deformation and curvature of an insert subsequentto placement in an eye with the insert curved so as to correspond to atleast the curvature of the lid along the cul-de-sac. The insert wasinitially flat and comprised a polypropylene suture retention structure110 and silicone support structure 120. The insert was oriented as shownand such that the upper silicone portion was placed over the lacrimalgland toward the superior temporal portion of the eye. The model eye isshown to indicate alignment of the insert to the eye and thecorresponding in situ formed curvature of the insert to the eye.

The insert was removed after being worn for a few days. The upperportion of the insert corresponding to the upper lid comprised acurvature 115C1 that curved posteriorly toward the patient so as tofollow the upper lid of the eye along the formix. The lower portion ofthe insert corresponding to the lower lid comprised a curvature 115C2that curved posteriorly toward the patient so as to follow the lower lidof the eye along the formix. The intermediate portions of the insertlocated between the upper and lower portions of the insert comprised acurvature 115C3 and a curvature 115C4 at locations corresponding to thelateral canthus and medial canthus. The intermediate portions comprisingthe curvature 115C3 and the curvature 115C4 are curved away from thepatient so as to curve anteriorly.

Several inserts removed from eyes have shown a saddle shape similar tothe insert shown in FIG. 25 and as described herein. This saddle shapeand curvatures corresponds to the saddle of astigmatism known in thefield of optics, for example. The in situ forming of the shape of themay provide decreased pressure and irritation to the eye and may provideimproved biocompatibility.

The in situ formed shapes can be used to determine a pre-insertion andpre-formed shape of the insert prior to placement on the eye. Thepre-formed insert may comprise an in situ formable material such aspolypropylene, for example, or a non-in situ formable material such as ametal wire or robust shape memory material, for example. The pre-formedinsert may comprise upper and lower portions curved toward the patientand intermediate nasal and temporal portions curved away from thepatient, for example.

FIGS. 26A and 26B show rates of release of prostaglandin comprisingbimatoprost from an insert comprising a silicone matrix. The estimatedrate of release for a matrix having 7% prostaglandin comprisingbimatoprost loaded on the insert is above 3.5 ug per day for at leastabout 90 days. The rate of release of prostaglandin comprisingbimatoprost was measured from a matrix comprising medical grade siliconehaving an approximate durometer of 10 A. The configuration of the insertand matrix is described in Table 3 with reverence to mono v.1 whichcomprises a 1 mm diameter silicone matrix extending along a 75 degreearc length. The surface area was 47.9 mm² and the volume 10.4 mm³. Forthe 7% loading the amount of drug loaded on the device was about 700 μg.The rate of release of about 0.9 ug/day for 90 days was measured and therate of release for 120 days was estimated.

The therapeutic agent was released for 70 days above 1 ug per day. Basedon Table 3, the matrix can be configured to release additional amountstherapeutic agent. For example, the rate of release can be increased bymore than 4× by extending the matrix 360 degrees around the suture.

FIG. 27 shows wash time and rates of release of therapeutic agent frommatrices having varying amounts of wash in a 70% isopropanol bath. Theexperiments were conducted with silicone rings having 7% prostaglandincomprising bimatoprost and medical grade silicone having a rateddurometer of Shore A 10 without drug. The elution rate for the unwashedmatrix (“0 wash”) was about 35 ug per day and decreased substantially.The elution rate for the matrix washed for 15 minutes was about 17 ugper day, after about 2 days, the matrix washed for 15 minutes releasedtherapeutic agent at a rate similar to the unwashed matrix, indicatingthat the 15 minute removed therapeutic agent from the surface and didnot remove detectable amounts of therapeutic agent from deeper portionsof the matrix. The 60 minute and 180 minute was matrices showed similarresults and an initial rate of release of about 13 ug per day whichdecreased to about 5 ug per day at 15 days. By day 14 the rate ofrelease was substantially the same for each of the unwashed matrix, thematrix washed for 15 minutes, matrix washed for 60 minutes, and thematrix washed for 180 minutes. This data indicates that washing thematrix in a solvent can decrease variability of the rate of release ofthe therapeutic agent.

FIG. 28 shows examples IOP and rates of therapeutic agent release inaccordance with embodiments. The graph shows IOP for days 59 to 69 of atest subject. The initial studies on the test subject appear to indicateit may be helpful to provide greater amounts of therapeutic agent thanwould be provided based on eye drop estimates. The IOP was measured andamounts of therapeutic agent estimated. The amount of therapeutic agentreleased was estimated by using paired devices such that the insertplaced in the eye had a corresponding “twin” insert. The twin insert wasplaced in a solution when the patient insert was placed in the eye. Themeasured rate of release of the twin placed in solution was used todetermine the rate of release of the insert placed in the eye.

The data of this small study indicate that in at least some instancesfor some patients, the target threshold amount of therapeutic agentreleased continuously from an insert placed in the eye may be greaterthan the amount provided to tissue by drops. It was observed thatproviding amounts of therapeutic agent greater than the estimated amountprovided by drops may provide an improved result. It was observed thatafter about sixty days the IOP had increased to about 19.5 mm Hg wasclose to the control eye, and the determined rate of release was about1.2 ug of prostaglandin comprising bimatoprost per day. The insert wasreplaced with a second insert providing a rate of release of about 1.6to 2.5 ug per day based on twin measurements, and the IOP decreased towithin a range from about 17 to 18 mm Hg. The second insert was replacedwith a third insert providing over 3.8 to 4 ug per day based on twinmeasurements, and the IOP decreased further to within a range from 14.5to 16 mm Hg.

These preliminary data indicate that at least about 3 ug per day ofprostaglandin such as bimatoprost may provide an improved decrease inIOP as compared with less than 3 ug per day, for example.

Based on the teachings described herein, a person of ordinary skill inthe art can determine empirically the amount of therapeutic agent to beprovided for an extended time, for example the amount of prostaglandinsuch as bimatoprost eluted for six months so as to provide therapeuticrelief from a disease condition of the eye such as glaucoma.

The embodiments as described herein are provided as non-limitingexamples and can be combined and modified in many ways. In manyembodiments, the insert is provided with a drug delivery matrix materialhaving a one or more of a stiffness or spring bias corresponding to theabove described retention structures, such that the insert can beprovided without a skeletal structure and provide the function of theskeletal structure. For example, the drug delivery matrix may comprisematerials having a durometer and cross-sectional dimensions so as toprovide the function of the retention structure. Alternatively or incombination, a support structure as described herein such as the drugdelivery matrix can be provided over the retention structure asdescribed herein, for example.

The embodiments as described herein can be configured in many ways, andmay comprise portions coated with the drug release matrix, and maycomprise a 75 degree, a 180 degree or a 360 degree drug release matrixfor example. In many embodiments, the insert can be coated with acushioning material, for example a soft silicone.

Each of the above-described embodiments can be combined with the otherembodiments in accordance with the teachings described herein, and aperson of ordinary skill in the art will readily recognize many suchcombinations. For example, one or more elements of one or moreembodiments described in any one figure can be combined with any one ormore elements of another figure, such that the inventors have describedand reserve the right to claim any combination of elements, structures,functions, and steps as described herein.

While the exemplary embodiments have been described in some detail, byway of example and for clarity of understanding, those of ordinary skillin the art will recognize that a variety of modifications, adaptations,and changes may be employed. Hence, the scope of the present disclosureshall be limited solely by the appended claims.

What is claimed is:
 1. An apparatus to treat an eye of a patient, theeye having a conjunctiva, the apparatus comprising: a first,substantially ring-like structure adapted to be positioned onto ananterior surface of, and outside an optical zone of, the eye at leastpartially underneath at least one of the upper and lower eyelids, thefirst structure comprising at least one retention structure configuredto guide the apparatus along a conjunctival sac when the eye moves; anda second structure supported by at least a portion of at least oneretention structure disposed through the second structure, wherein thesecond structure is formed of a material softer than the first structurethereby presenting a softer, cushioning surface available to contact theeye, and wherein the second structure comprises at least one therapeuticagent disposed on or dispersed into the material of the secondstructure; wherein the apparatus has a first shape prior to placementonto the eye and, the apparatus conforms in situ to a second shape whenplaced for a period of time, and wherein, after being removed from theeye, the first structure is configured to retain substantially thesecond shape.
 2. The apparatus of claim 1, wherein the apparatuscomprises an amount of resistance to form one or more of a fold, apocket, or deformation of the conjunctiva so as to receive and retainthe insert.
 3. The apparatus of claim 1, wherein the apparatus comprisesa hoop having a hoop strength to resist deflection when placed on theeye.
 4. The apparatus of claim 1, wherein the apparatus comprises areversibly deflectable hoop having a circumference sized to fit the eye.5. The apparatus of claim 1, wherein the at least one retentionstructure is sized to be received within one or more folds of theconjunctiva to hold the at least one retention structure on the eye foran extended time.
 6. The apparatus of claim 5, wherein the at least oneretention structure is adapted to move within the conjunctival sac andremain on the eye continuously for at least about one week.
 7. Theapparatus of claim 5, wherein the at least one retention structure isadapted to move within the conjunctival sac and remain on the eyecontinuously for at least about one month.
 8. The apparatus of claim 5,wherein the at least one retention structure is adapted to move withinconjunctival sacs and remain on eyes of a population continuously for atleast about one month.
 9. The apparatus of claim 5, wherein the at leastone retention structure is adapted to move within the conjunctival sacwithout attaching to the eye and remain on the eye continuously for atleast about one month.
 10. The apparatus of claim 5, wherein the one ormore folds of the conjunctiva comprise a plurality of folds extendingalong a bulbar conjunctiva of the eye and a plurality of folds extendingalong a palpebral conjunctiva of the eye.
 11. The apparatus of claim 5,wherein the at least one retention structure comprises a hoop having ahoop strength to resist deflection when placed on the eye.
 12. Theapparatus of claim 1, wherein the second structure comprises a softmaterial disposed along at least a portion of the first structure atlocations corresponding to one or more of a lacrimal gland or a carunclewhen the apparatus is positioned on the eye.
 13. The apparatus of claim12, wherein the at least one retention structure is shaped with aninward extension to inhibit irritation of the lacrimal gland.
 14. Theapparatus of claim 12, wherein the at least one retention structure isshaped with an inward extension to inhibit contact with the caruncle ofthe eye.
 15. The apparatus of claim 12, wherein the retention structureis shaped with a first inward extension to inhibit irritation of thelacrimal gland and a second inward extension to inhibit contact with thecaruncle of the eye.
 16. An apparatus adapted to be positioned onto ananterior surface of an eye outside an optical zone of the eye at leastpartially underneath at least one of the upper and lower eyelids totreat the eye, the apparatus comprising: a support structure comprisingat least one therapeutic agent disposed on or dispersed into a materialof the support structure; and a retention structure at least a portionof which is disposed through the support structure, wherein the materialof the support structure is softer than the retention structure therebypresenting a softer surface available to contact the eye, and whereinthe retention structure provides a resistance to deflection of theapparatus such that the apparatus has a first shape prior to placementonto the eye, conforms in situ to a second shape when placed on the eyefor a period of time, and after being removed from the eye retainssubstantially the second shape.
 17. The apparatus of claim 16, whereinthe resistance to deflection comprises a self-loading resistance todeflection and provides a self-loading deflection angle within a rangefrom about 0 degrees to about 70 degrees.
 18. The apparatus of claim 16,wherein the retention structure is an annular, ring-like structure andthe at least a portion of the retention structure disposed through thesupport structure comprises 75, 80, 80, 180, 270, or 360 degrees of theannular retention structure.
 19. The apparatus of claim 18, wherein theretention structure is a suture formed of polypropylene or nylon. 20.The apparatus of claim 19, wherein the material of the support structurecomprises a silicone matrix.